Substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepanes useful for the treatment of allergic diseases

ABSTRACT

The present invention relates to novel 4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives of formula (1):                    
     and stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonist. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn&#39;s disease and ulcerative colitis; asthma; bronchitis; and emesis.

This application is a continuation-in-part of U.S. application Ser. No.09/513,847, filed Oct. 29, 1997, now U.S. Pat No. 6,194,406, which is acontinuation-in-part of U.S. application Ser. No. 08/736,411, filed Oct.24, 1996, now abandoned, which claims the benefit of U.S. Provisionalapplication serial No. 60/070,907, filed Dec. 20, 1995.

The present invention relates to novel substituted4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives (herein referred toas a compound or compounds of formula (1)) and their use as histaminereceptor antagonists and tachykinin receptor antagonists. Suchantagonists are useful in the treatment of asthma; bronchitis;inflammatory bowel diseases, including Crohn's disease and ulcerativecolitis; allergic rhinitis, including seasonal rhinitis and sinusitis;allergies; and emesis.

The compounds of the present invention are useful in theirpharmacological activities, such as histamine receptor antagonism andtachykinin receptor antagonism. Antagonism of histamine responses can beelicited through blocking of histamine receptors. Antagonism oftachykinin responses can be elicited through blocking of tachykininreceptors. One object of the present invention is to provide new anduseful antagonists of histamine. A further object of the presentinvention is to provide new and useful antagonists of tachykinins. Aparticular object of the present invention are those compounds thatexhibit both histamine and tachykinin receptor antagonism.

SUMMARY OF THE INVENTION

The present invention provides novel substituted4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives of the formula:

wherein

m is 2 or 3;

n is 0 or 1;

q is 1 or 2;

r is 0 or 1;

G₁ is —CH₂— or —C(O)—;

G₂ is —CH₂—, —CH(CH₃)— or —C(O)—;

G₃ is —CH₂— or —C(O)—;

Ar₁ is a radical chosen from the group consisting of

wherein

R₁ is from 1 to 3 substituents each independently chosen from the groupconsisting of hydrogen, halogen, hydroxy, —CF₃, C₁-C₆ alkyl, and C₁-C₆alkoxy;

R₂ is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

Ar₂ is a radical selected from the group consisting of

wherein

z is 1 or 2;

R₂₀ is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, hydroxy, halogen, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

R₃is from 1 to 3 substituents each independently chosen from the groupconsisting of hydrogen, hydroxy, halogen, —OCF₃, C₁-C₆ alkyl, C₁-C₆alkoxy, —(CH₂)_(d)S(O)_(b)R₂₂, —(CH₂)_(e)CN, —O(CH₂)_(c)CO₂R₂₃, —NH₂,—NHC(O)CH₃, —NHSO₂CH₃ wherein c is an integer from 1 to 5; b is 0, 1, or2; d is 0 or 1; e is 0 or 1; R₂₂ is C₁-C₄ alkyl; and R₂₃ is hydrogen orC₁-C₄ alkyl;

R₂₁ is hydrogen or a radical chosen from the group consisting of

wherein

f is 0 or 1;

R₂₅is hydrogen or —CH₃;

R₂₄is selected from the group consisting of hydrogen, C₁-C₄ alkyl, —CF₃,phenyl, S(O)_(x)R₂₆, and CH₂N(CH₃)₂ wherein x is 0, 1, or 2; R₂₆ isC₁-C₄ alkyl;

R₄ is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, —CF₃, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

R₅ is chosen from the group consisting of hydrogen, C₁-C₄ alkyl,—(CH₂)_(w)—O—(CH₂)_(t)CO₂R₈, —(CH₂)_(j)CN, —(CH₂)_(u)CO₂R₆,—(CH₂)_(u)C(O)NR₁₆R₁₇, —(CH₂)_(u)C(O)CH₃, —(CH₂)_(p)Ar₃,—(CH₂)_(w)—O—R₇, —CH₂CH═CHCF₃, —(CH₂)₂CH═CH₂, —CH₂CH═CH₂, —CH₂CH═CHCH₃,—CH₂CH═CHCH₂CH₃, —CH₂CH═C(CH₃)₂, and —(CH₂)_(g)S(O)_(k)R₁₉,

wherein

w is an integer from 2 to 5;

t is an integer from 1 to 3;

j is an integer from 1 to 5;

u is an integer from 1 to 5;

p is an integer from 1 to 4;

g is 2 or 3;

k is 0, 1, or 2;

R₈ is hydrogen or C₁-C₄ alkyl;

R₆ is hydrogen or C₁-C₄ alkyl;

R₁₆ is hydrogen or C₁-C₄ alkyl;

R₁₇ is hydrogen or C₁-C₄ alkyl;

R₁₉ is C₁-C₄ alkyl or a radical of the formula

Ar₃ is a radical chosen from the group consisting of

wherein

R₉ is from 1 to 3 substituents each independently chosen from the groupconsisting of hydrogen, halogen, —CF₃, C₁-C₆ alkyl, C₁-C₆ alkoxy, and—CO₂R₁₃ wherein R₁₃ is chosen from the group consisting of hydrogen andC₁-C₄ alkyl;

R₁₀ is from 1 to 2 substituents each independently chosen from the groupconsisting of hydrogen, halogen, C₁-C₆ alkyl, and C₁-C₆ alkoxy;

R₁₁ is chosen from the group consisting of hydrogen, —CH₃, and —CH₂OH;

R₁₂ is chosen from the group consisting of hydrogen, C₁-C₄ alkyl, andbenzyl;

R₁₈ is chosen from the group consisting of hydrogen, halogen, —CH₃, and—CH₂OH;

R₇ is hydrogen, C₁-C₄ alkyl, —(CH₂)_(y)—CF₃, —CH₂CN or a radical chosenfrom the group consisting of

wherein

v is an integer from 1 to 3;

y is an integer from 0 to 2;

R₁₄ is chosen from the group consisting of hydrogen, halogen, C₁-C₄alkyl, and. —CO₂R₁₅ wherein R₁₅ is hydrogen or C₁-C₄ alkyl;

provided that when G₁ is —C(O)— then G₂ is either —CH₂— or —CH(CH₃)— andG₃ is —CH₂—;

further provided that when G₂ is —C(O)— then G₁ is —CH₂— and G₃ is—CH₂—;

still further provided that when G₃ is —C(O)— then G₁ is —CH₂— and G₂ iseither —CH₂— or —CH(CH₃)—;

or stereoisomers, or pharmaceutically acceptable salts thereof.

As is appreciated by one of ordinary skill in the art the compounds ofthe formula (1) may exist as stereoisomers depending on the nature ofthe substituents present. Any reference in this application to one ofthe compounds of the formula (1) is meant to encompass either specificstereoisomers or a mixture of stereoisomers. Where indicated, thecompounds follow the designation of (+)- and (−)- or (R)- and (S)- or(E)- and (Z)- for the stereochemistry of compounds represented byformula (1). It is specifically recognized that in the substituted3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)pyrrolidines,substituted3-arylmethyl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)pyrrolidines,substituted3-aryl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)piperidines,and substituted3-arylmethyl-3-((1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)alkyl)piperidines;the 3-position of the pyrrolidine or piperidine is asymmetric, and maybe in the (R)- or (S)-configuration, or may be a mixture thereof. It isspecifically recognized that compounds of formula (1) in which G₂ is—CH(CH₃)— are asymetric at the methyl bearing carbon and may be in the(R)- or (S)-configuration, or may be a mixture thereof. It isspecifically recognized that compounds of formula (1) in which R₅ is—CH₂CH═CHCF₃, —CH₂CH═CHCH₃, and —CH₂CH═CHCH₂CH₃ may exist asstereoisomers and may be in the (E)- or (Z)-configuration, or may be amixture thereof.

The specific stereoisomers can be prepared by stereospecific synthesisusing enantiomerically or geometrically pure or enantiomerically orgeometrically enriched starting materials. The specific stereoisomers ofeither starting materials or products can be resolved and recovered bytechniques known in the art, such as chromatography on chiral stationaryphases, enzymatic resolution, or fractional recrystallization ofaddition salts formed by reagents used for that purpose. Useful methodsof resolving and recovering specific stereoisomers are know in the artand described in Stereochemistry of Organic Compounds, E. L. Eliel andS. H. Wilen, Wiley (1994) and Enantiomers, Racemates, and Resolutions,J. Jacques, A. Collet, and S. H. Wilen, Wiley (1981).

As is appreciated by one of ordinary skill in the art some of thecompounds of the formula (1) may exist as tautomers. Any reference inthis application to one of the tautomers of compounds of the formula (1)is meant to encompass every tautomeric form and mixtures thereof.

As used in this application:

a) the term “halogen” refers to a fluorine atom, chlorine atom, bromineatom, or iodine atom;

b) the term “C₁-C₆ alkyl” refers to a branched or straight chained alkylradical containing from 1 to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, pentyl,hexyl, cyclopentyl, cyclohexyl, etc;

c) the term “C₁-C₆ alkoxy” refers to a straight or branched alkoxy groupcontaining from 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, t-butoxy, pentoxy, hexoxy,cyclopentoxy, cyclohexoxy, etc;

d) the designations —C(O)— or —(O)C— refer to a carbonyl group of theformula:

e) the designation “” refers to a bond for which the stereochemistry isnot designated;

f) as used in the examples and preparations, the following terms havethe meanings indicated: “kg” refers to kilograms, “g” refers to grams,“mg” refers to milligrams, “μg” refers to micrograms, “mol” refers tomoles, “mmol” refers to millimoles, “nmole” refers to nanomoles, “L”refers to liters, “mL” or “ml” refers to milliliters, “μL” refers tomicroliters, “° C.” refers to degrees Celsius, “R_(f)” refers toretention factor, “mp” refers to melting point, “dec” refers todecomposition, “bp” refers to boiling point, “mm of Hg” refers topressure in millimeters of mercury, “cm” refers to centimeters, “nm”refers to nanometers, “[α]² _(D) ⁰” refers to specific rotation of the Dline of sodium at 20° C. obtained in a 1 decimeter cell, “c” refers toconcentration in g/mL, “THF” refers to tetrahydrofuran, “DMF” refers todimethylformamide, “brine” refers to a saturated aqueous sodium chloridesolution, “M” refers to molar, “mM” refers to millimolar, “μM” refers tomicromolar, “nM” refers to nanomolar, “psi” refers to pounds per squareinch, “TLC” refers to thin layer chromatography, “HPLC” refers to highperformance liquid chromatography, “HRMS” refers to high resolution massspectrum, “lb” refers to pounds, “gal” refers to gallons, “L.O.D.”refers to loss on drying, “μCi” refers to microcuries, “i.p.” refers tointraperitoneally, “i.v.” refers to intravenously, and “DPM” refers todisintegrations per minute;

g) the designation

refers to a phenyl or a substituted phenyl and it is understood that theradical is attached at the 1-position and the substituent orsubstituents represented by R can be attached in any of the 2, 3, 4, 5,or 6 positions;

h) the designation

refers to a pyridine, substituted pyridine, pyridyl or substitutedpyridyl and it is understood that the radical can be attached at eitherthe 2-position, the 3-position, or the 4-position, it is furtherunderstood that when the radical is attached at the 2-position thesubstituent or substituents represented by R can be attached in any ofthe 3, 4, 5, or 6 positions, that when the radical is attached at the3-position the substituent or substituents represented by R can beattached in any of the 2, 4, 5, or 6 positions, and that when theradical is attached at the 4-position the substituent or substituentsrepresented by R can be attached in any of the 2, 3, 5, or 6 positions;

i) the designation

refers to a thiophene or thienyl and it is understood that the radicalis attached at the 2 or 3-positions;

j) the designation

refers to a naphthalene, substituted naphthalene, naphthyl orsubstituted naphthyl and it is understood that the radical can beattached at either the 1-position or the 2-position, it is furtherunderstood that when the radical is attached at the 1-position thesubstituent or substituents represented by R can be attached in any ofthe 2, 3, 4, 5, 6, 7, or 8 positions and that when the radical isattached at the 2-position the substituent or substituents representedby R can be attached in any of the 1, 3, 4, 5, 6, 7, or 8 positions:

k) the term “enantiomeric excess” or “ee” refers to the percent by whichone enantiomer, El , is in excess in a mixture of the two enantiomers,El plus E2, such that

{(E1−E2)÷(El+E2)}×100%=ee;

l) the term “C₁-C₄ alkyl” refers to a saturated straight or branchedchain alkyl group containing from 1-4 carbon atoms and includes methyl,ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, and t-butyl;

m) the designations —CO₂R and —C(O)OR refer to a group of the formula:

n) the designation —C(O)NRR refer to a group of the formula:

o) the designation

refers to a furan or furyl and it is understood that the radical isattached at either the 2-position or 3-position;

p) the designation “” refers to a bond that protrudes forward out of theplane of the page;

q) the designation “” refers to a bond that protrudes backward out ofthe plane of the page;

r) the term “pharmaceutically acceptable salts thereof” refers to eitheran acid addition salt or a basic addition salt.

The expression “pharmaceutically acceptable acid addition salts” isintended to apply to any non-toxic organic or inorganic acid additionsalt of the base compounds represented by formula (1) or any of itsintermediates. Illustrative inorganic acids which form suitable saltsinclude hydrochloric, hydrobromic, sulphuric, and phosphoric acid andacid metal salts such as sodium monohydrogen orthophosphate, andpotassium hydrogen sulfate. Illustrative organic acids which formsuitable salts include the mono-, di-, and tricarboxylic acids.Illustrative of such acids are for example, acetic, glycolic, lactic,pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic,cinnamic, salicyclic, 2-phenoxybenzoic, p-toluenesulfonic acid, andsulfonic acids such as methane sulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either a hydrated orsubstantially anhydrous form. In general, the acid addition salts ofthese compounds are soluble in water and various hydrophilic organicsolvents, and which in comparison to their free base forms, generallydemonstrate higher melting points.

The expression “pharmaceutically acceptable basic addition salts” isintended to apply to any non-toxic organic or inorganic basic additionsalts of the compounds represented by formula (1) or any of itsintermediates. Illustrative bases which form suitable salts includealkali metal or alkaline-earth metal hydroxides such as sodium,potassium, calcium, magnesium, or barium hydroxides; ammonia, andaliphatic, alicyclic, or aromatic organic amines such as methylamine,dimethylamine, trimethylamine, and picoline.

Preferred embodiments of formula (1) are given below:

1) Compounds wherein q is 1 are preferred;

2) Compounds wherein r is 0 are preferred;

3) Compounds wherein m is 2 are preferred;

4) Compounds wherein G₁ is —CH₂— are preferred;

5) Compounds wherein G₂ is —C(O)— are preferred;

6) Compounds wherein R₅ is —(CH₂)_(w)—O—R₇ are preferred;

7) Compounds wherein R₅ is —(CH₂)_(p)Ar₃ are preferred.

It is understood that further preferred embodiments of formula (1) canbe selected by requiring one or more of the preferred embodiments 1through 7 of formula (1) or by reference to examples given herein.

Examples of compounds encompassed by the present invention include thefollowing. It is understood that the examples encompass the specificstereoisomers and diastereomers, where applicable, of the compound andmixtures thereof. This list is meant to be representative only and isnot intended to limit the scope of the invention in any way:

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,5-Dimethoxy-4-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4-Dimethoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-(4-Carboxypropyl)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazeparn-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3-(1H-Tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(5-methylsulfonyltetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(5-trifluormethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

1-(2-Methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(4H-triazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(3,5-dimethyl-4H-triazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-methylthiobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

1-(3-Methoxy-4,5-methylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3-Methoxy-4,5-ethylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-(1H-tetrazol-5-yl)butyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-trifluormethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-methylsulfonamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(methylthiomethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(cyanomethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-fluorobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1l,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine;

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine;

1-(-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlororphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2-propyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2-propyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-oxobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-methylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-methylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-5-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimnidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(fur-2-ylmethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-3,4dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-4-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-4-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(5-methylfur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-methy-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-methy-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-ethyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-ethyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1(2-(trifluoromnethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-Benzoyl-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-Benzoyl-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine;

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine.

The compounds of formula (1) may be synthesized by use of the followingsynthetic procedures to produce intermediates or final compounds of theinvention:

Reaction Scheme A.1 relates to the synthesis of compounds of formula (1)by alkylation of intermediates derived from alcohols of structure 2.

Reaction Scheme A.2 relates to the synthesis of compounds of formula (1)by reductive amination of aldehydes derived from alcohols of structure2.

Reaction Scheme A.3 relates to the synthesis of compounds of formula (1)by aroylation or alkylation of intermediates derived from alcohols ofstructure 40.

Reaction Scheme B relates to the synthesis of alcohols of structure 2 inwhich G₃ is —CH₂— used as a starting material in Reaction Schemes A.1and A.2 and intermediates of structure 11 used to prepare alcohols ofstructure 40 in Reaction Scheme A.3.

Reaction Scheme C relates to a synthesis of alcohols of structure 2 inwhich m is 2, q is 1, r is 0, and G₃ is —CH₂— and relates to thesynthesis of intermediates of structure 8 used to prepare alcohols ofstructure 2 in Reaction Scheme B and intermediates of structure 18 usedto prepare alcohols of structure 40 in Reaction Scheme A.3.

Reaction Scheme D relates to a synthesis of alcohols of structure 2 inwhich r is 1 and G₁ is —CH₂— used as a starting material in ReactionScheme A.1 and A.2 and intermediates of structure 26 used to preparealcohols of structure 40 in Reaction Scheme A.3.

Reaction Scheme E relates to a synthesis of alcohols of structure 2 inwhich r is 0 and G₁ is —CH₂— used as a starting material in ReactionScheme A.1 and A.2 and intermediates of structure 35 used to preparealcohols of structure 40 in Reaction Scheme A.3.

A general synthetic procedure for preparing these compounds of formula(1) is set forth in Reaction Scheme A.1. The reagents and startingmaterials are readily available to one of ordinary skill in the art. InReaction Scheme A.1, all substituents, unless otherwise indicated, areas previously defined.

In Reaction Scheme A.1, step 1, the hydroxy group of an appropriatealcohol of structure 2 is converted to an appropriate leaving group togive a compound of structure 2a.

An appropriate alcohol of structure 2 is one in which thestereochemistry is as desired in the final product of formula (1) and m,n, q, r, G₁, G₂, G₃, Ar₁ and Ar₂ are as desired in the final product offormula (1). Alternately, an appropriate alcohol of structure 2 can beone in which the stereochemistry gives rise after resolution tostereochemistry as desired in the final product of formula (1) and m, n,q, r, G₁, G₂, G₃, Ar₁ and Ar₂ are as desired in the final product offormula (1). An appropriate alcohol of structure 2 can also be one inwhich the stereochemistry is as desired in the final product of formula(1); and m, n, q, r, G₁, G₂, and G₃ are as desired in the final productof formula (1); and Ar₁ and/or Ar₂ gives rise upon deprotection to Ar₁and/or Ar₂ as desired in the final product of formula (1). Alternately,an appropriate alcohol of structure 2 can also be one in which thestereochemistry gives rise after resolution to stereochemistry asdesired in the final product of formula (1); and m, n, q, r, G₁, G₂, andG₃ are as desired in the final product of formula (1); and Ar₁ and/orAr₂ gives rise upon deprotection to Ar₁ and/or Ar₂ as desired in thefinal product of formula (1). Appropriate alcohols of structure 2 can beprepared as described herein and in International Patent Application(PCT) No. WO 94/26735, published Nov. 24, 1994.

An appropriate leaving group, L₁, is one which can be displaced by a4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 to give rise to acompound of formula (1). Appropriate leaving groups, L₁, include but arenot limited to chloro, bromo, iodo, mesylate, tosylate,benzenesulfonate, trifluoromethanesulfonate, and the like. Theconversion of hydroxy groups to leaving groups such as chloro, bromo,iodo, mesylate, tosylate, benzenesulfonate, andtrifluoromethanesulfonate is well known and appreciated in the art.

For example, compounds in which L₁ is bromo are formed by contacting anappropriate alcohol of structure 2 with 1.0 to 1.5 molar equivalents ofcarbon tetrabromide and 1.0 to 1.75 molar equivalentstriphenylphosphine. (P. J. Kocienski et al. J. Org. Chem. 42, 353-355(1977)). The reaction is carried out by combining the alcohol ofstructure 2 with carbon tetrabromide in a suitable solvent, such asdichloromethane or chloroform and then adding a solution oftriphenylphosphine in a suitable solvent, such as dichloromethane orchloroform. Generally the reaction is carried out at temperatures offrom −10° C. to ambient temperature. Generally, the reactions requirefrom 5 minutes to 24 hours. The product can be isolated and purified bytechniques well known in the art, such as extraction, evaporation,trituration, chromatography, and recrystallizationa.

Compounds in which L₁ is bromo are also formed by contacting anappropriate alcohol of structure 2 with a slight molar excess oftriphenylphosphine dibromide. (R. F Borch et al. J. Am. Chem. Soc. 99,1612-1619 (1977)). The reaction may be carried out by contacting anappropriate alcohol of structure 2 with preformed triphenylphosphinedibromide. The reaction is carried out in a suitable solvent, such astetrahydrofuran and diethyl ether. The reaction is carried out in thepresence of a suitable base, such as pyridine. Generally the reaction iscarried out at temperatures of from 0° C. to 50° C. Generally, thereactions require from 5 minutes to 24 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

Alternately, for example, compounds in which L₁ is mesylate are formedby contacting an appropriate alcohol of structure 2 with a molar excessof methanesulfonyl chloride. The reaction is carried out in a suitablesolvent, such as acetonitrile, dichloromethane, chloroform, toluene,benzene, or pyridine. The reaction is carried out in the presence of asuitable base, such as triethylamine, diisopropylethylamine, orpyridine. Generally the reaction is carried out at temperatures of from−20° C. to 50° C. Generally, the reactions require from 1 hour to 24hours. The product can be isolated and purified by techniques well knownin the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

Compounds of structure 2a in which L₁ is iodo can be prepared fromcompounds of structure 2a in which L₁ is mesylate, chloro, or bromo byan exchange reaction, such as the Finkelstein reaction.

For example, a compound of structure 2a in which L₁ is mesylate, chloro,or bromo is contacted with from 1.0 to 10.0 molar equivalents of aniodide salt, such as sodium iodide or potassium iodide. The reaction iscarried out in a suitable solvent, such as acetone, butanone,tetrahydrofuran, tetrahydrofuran/water mixtures, toluene, andacetonitrile. Generally, the reaction is carried out at temperatures offrom ambient temperature to the refluxing temperature of the solvent.Generally, the reactions require from 1 hour to 24 hours. The productcan be isolated and purified by techniques well known in the art, suchas extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme A.1, step 2, the compound of structure 2a reacts withan appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound ofstructure 3 or a salt thereof to give a protected compound of formula(1) or a compound of formula (1).

An appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 orsalt thereof is one in which R₄ and R₅ are as desired in the finalproduct of formula (1) or R₅ gives rise after deprotection and/ormodification to R₅ as desired in the final product of formula (1).Appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 arewell known and appreciated in the art. Appropriate4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 may be preparedby methods known in the art such as described in J. Med Chem. 29,1178-1183 (1986), Chem. Pharm. Bull., 37 962-966 (1989), and Tet. Lets.,38, 5607-5610 (1997); and by methods analogous to those methods and tothose described herein by carrying out suitable deprotections,protections, and alkylations, and modifications, such as the reductionof esters, as are well known in the art, in the order and numberrequired for formation of an appropriate4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3.

For example, the compound of structure 2a is contacted with anappropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of structure3 or salt thereof to give a protected compound of formula (1) or acompound of formula (1). The reaction is carried out in a suitablesolvent, such as dioxane, tetrahydrofuran, tetrahydrofuran/watermixtures, acetone, acetone/water mixtures, ethyl acetate, ethylacetate/water mixtures, pyridine, acetonitrile, toluene, toluene/watermixtures, chlorobenzene, or dimethylformamide, with acetonitrile beingpreferred. The reaction is carried out in the presence of from 1.0 to6.0 molar equivalents of a suitable base, such as sodium carbonate,sodium bicarbonate, potassium carbonate, potassium bicarbonate,triethylamine, pyridine, or diisopropylethylamine, withdiisopropylethylamine being preferred. When a salt of an appropriate4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 is used, a molarexcess of a suitable base may be required to absorb the acid liberatedfrom the salt. The reaction may be facilitated by the addition of acatalytic amount, 0.1 to 0.5 molar equivalents, of an iodide salt, suchas sodium iodide, potassium iodide, or tetrabutyl ammonium iodide. Thereaction is generally carried out at temperatures of from ambienttemperature to the refluxing temperature of the solvent. Generally, thereactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme A.1, optional step 3, a compound of formula (1) or aprotected compound of formula (1) in which R₅ is hydrogen is modified togive a compound of formula (1) or a protected compound of formula (1) inwhich R₅ is not hydrogen. Also encompassed by Reaction Scheme A.1,optional step 3, a protected compound of formula (1) is deprotected togive a compound of formula (1).

A modification reaction, encompasses the formation of amides and thealkylation of the benzimidazole nitrogen. The formation of amides fromesters and acids is well known and appreciated in the art. Thealkylation of a benzimidazole nitrogen using a suitable alkylating agentis well known and appreciated in the art. An alkylation of abenzimidazole nitrogen encompasses the Michael addition usingα,β-unsaturated electrophiles. A suitable alkylating agent is one whichtransfers a group R₅ as desired in the final product of formula (1) or aprotected group R₅ which gives rise after deprotection to R₅ as desiredin the final product of formula (1).

For example, a compound of formula (1) in which R₅ is hydrogen iscontacted with a suitable alkylating agent. A suitable alkylating agentis one which transfers a group R₅ as is desired in the final product offormula (1). Suitable alkylating agent include but are not limited to4-fluorobenzyl bromide, 4-fluorobenzyl chloride, 2-(chloromethyl)furan,3-(chloromethyl)furan, 2-(bromomethyl)thiophene,3-(chloromethyl)thiophene, 2-(chloromethyl)pyridine,3-(chloromethyl)pyridine, 4-(chloromethyl)pyridine, 2-chlorethyl ethylether, 2-chloroethyl methyl ether, benzyl chloride, 4-methoxybenzylchloride, 5-(ethoxycarbonyl)-2-(chloromethyl)furan, ethyl chloroacetate,t-butyl bromoacetate, methyl bromoacetate, methyl iodide, ethyl iodide,propyl iodide, isopropyl iodide, butyl bromide, 2-isopropyloxyethylchloride, 2-phenoxyethyl chloride, 2-(4-fluorophenoxy)ethyl bromide,3-(4-fluorophenoxy)propyl bromide, methyl 2-(chloromethyl) benzoate,methyl 3-(chloromethyl)benzoate, methyl 4-(chloromethyl)benzoate, ethyl2-(chloromethyl)benzoate, propyl 2-(chloromethyl)benzoate,N,N-dimethyl-4-(chloromethyl)benzamide, iodoacetamide, allyl chloride,allyl bromide, (E)-1-chlorobut-2-ene, (Z)-1-chlorobut-2-ene,1-chloro-3-methylbut-2-ene, 2-(2,2,2-trifluoroethoxy)ethyl chloride,2-trifluoromethoxyethyl chloride, 1-chloro-4,4,4-trifluorobut-2-ene,(E)-1-chloropent-2-ene, (Z)-1-chloropent-2-ene, acrylonitrile, methylacrylate, t-butyl acrylate, methyl vinyl sulfone, ethyl vinyl sulfone,phenyl vinyl sulfone, and the like. The reaction is carried out in asuitable solvent, such as dioxane, tetrahydrofuran,tetrahydrofuran/water mixtures, acetone, or acetonitrile. The reactionis carried out in the presence of from 1.0 to 6.0 molar equivalents of asuitable base, such as sodium hydride, potassium hydride,sec-butyllithium, sodium carbonate, sodium bicarbonate, potassiumcarbonate, potassium bicarbonate, triethylamine,1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene,potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, ordiisopropylethylamine; with potassium hydride being preferred when thealkylating agent is an alkyl halide and sec-butyllithium being preferredwhen the alkylating agent is an Micheal accepter. The reaction isgenerally carried out at temperatures of from −78° C. to the refluxingtemperature of the solvent. Generally, the reactions require 1 to 72hours. The product can be isolated and purified by techniques well knownin the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

A deprotection reaction, such as the removal of hydroxy protectinggroups or hydrolysis of an ester, utilizing suitable protecting groupssuch as those described in Protecting Groups in Organic Synthesis by T.Greene is well known and appreciated in the art.

A general synthetic procedure for preparing the compounds of formula (1)by reductive amination is set forth in Reaction Scheme A.2. The reagentsand starting materials are readily available to one of ordinary skill inthe art. In Scheme A.2, all substituents, unless otherwise indicated,are as previously defined. For the preparation of compounds of formula(1) in which Ar₁ is pyrid-2-yl the reductive amination as set forth inReaction Scheme A.2 is preferred.

In Reaction Scheme A.2, step 1, an appropriate alcohol of structure 2 isoxidized to an aldehyde of structure 2b by the method of Swern. (A. J.Mancuso et al., J. Org. Chem., 43 2480-2482 (1978), C. M. Amon, J. Org.Chem., 52, 4851-4855 (1987), and T. T. Tidwell, Synthesis, 857-870(1990). An appropriate alcohol of structure 2 is as described inReaction Scheme A.1, step 1.

For example, about two molar equivalents of dimethyl sulfoxide are addeddropwise to a solution of oxalyl chloride, pyridine sulfur trioxidecomplex, or trifluoroacetic anhydride in dichloromethane, atapproximately −60° C. After the addition is complete, the reaction isstirred for approximately two minutes. A molar equivalent of the alcoholof structure 2 either neat or as a solution in dichloromethane is added.After the addition is complete the reaction mixture is stirred for 5 to45 minutes, then about 3 to 5 molar equivalents of triethylamine isadded. The reaction mixture is allowed to stir with warming to ambienttemperature over 30 minutes to 2 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, chromatography, and recrystallization.

In Reaction Scheme A.2, step 2, the compound of structure 2b iscontacted with an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane ofstructure 3 or salt thereof in a reductive amination to give a protectedcompound of formula (1) or a compound of formula (1). An appropriate4-(1H-benzimidazol-2-yl)[1,4]diazepane of structure 3 or salt thereof isas defined in Reaction Scheme A-1.

For example, the compound of structure 2b is contacted with anappropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound of structure3 or salt thereof. The reaction is carried out using a molar excess of asuitable reducing agent such as sodium borohydride or sodiumcyanoborohydride with sodium cyanoborohydride being preferred. Reductiveaminations using secondary amines and aldehydes are well known andappreciated in the art. The reaction is carried out in a suitablesolvent, such as ethanol, methanol, dichloromethane, ordimethylformamide. Generally, the reaction is carried out attemperatures of from 0° C. to 50° C. Generally, the reactions require 1to 72 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, chromatography, andrecrystallization.

In Reaction Scheme A.2, optional step 3, a compound of formula (1) or aprotected compound of formula (1) in which R₅ is hydrogen is modified togive a a compound of formula (1) or a protected compound of formula (1)in which R₅ is not hydrogen and/or a protected compound of formula (1)is deprotected to give a compound of formula (1) as described inReaction Scheme A.1, optional step 3.

A general synthetic procedure for preparing the compounds of formula (1)in which G₁ and G₃ are —CH₂— is set forth in Reaction Scheme A.3. Thereagents and starting materials are readily available to one of ordinaryskill in the art. In Scheme A.3, all substituents, unless otherwiseindicated, are as previously defined.

In Reaction Scheme A.3, step 1, the hydroxy group of an appropriatealcohol of structure 40 is converted to an appropriate leaving group, asdescribed in Reaction Scheme A.1, step 1, to give a compound ofstructure 40a.

In Reaction Scheme A.3, step 1, an appropriate alcohol of structure 40is one in which the stereochemistry is as desired in the final productof formula (1) and m, q, r, and Ar₁ are as desired in the final productof formula (1) and G₁ and G₃ are —CH₂—. Alternately, an appropriatealcohol of structure 40 can be one in which the stereochemistry givesrise after resolution to stereochemistry as desired in the final productof formula (l) and m, q, r, and Ar₁ are as desired in the final productof formula (1) and G₁ and G₃ are —CH₂—. An appropriate alcohol ofstructure 40 can also be one in which the stereochemistry is as desiredin the final product of formula (1); and m, q, and r are as desired inthe final product of formula (1) and G₁ and G₃ are —CH₂—; and Ar₁ givesrise upon deprotection to Ar₁ as desired in the final product of formula(1). Alternately, an appropriate alcohol of structure 40 can also be onein which the stereochemistry gives rise after resolution tostereochemistry as desired in the final product of formula (1); and m,q, and r are as desired in the final product of formula (1) and G₁ andG₃ are —CH₂—; and Ar₁ gives rise upon deprotection to Ar₁ as desired inthe final product of formula (1).

An appropriate alcohol of structure 40 can be prepared by protecting thepyrrolidine or piperidine nitrogen of compounds of structure 11(Reaction Scheme B), compounds of structure 26 (Reaction Scheme D), andcompounds of structure 35 (Reaction Scheme E); in which the hydroxyprotecting group has been removed; and compounds of structure 18(Reaction Scheme C). The selection and use of a suitable amineprotecting group, Pg₃, such as those described in Protecting Groups inOrganic Synthesis by T. Greene are well known and appreciated in theart. In Reaction Scheme A.3 the use of benzamide and carbamateprotecting groups, such as benzoyl, t-butoxycarbonyl and ethoxycarbonyl,is preferred. Reaction Scheme A.3 the use of benzamide protectinggroups, such as benzoyl is more preferred.

In Reaction Scheme A.3, step 2, the compound of structure 40a reactswith an appropriate 4-(1H-benzimidazol-2-yl)[1,4]diazepane compound ofstructure 3 or a salt thereof, as described in Reaction Scheme A.1, step2, to give a protected compound of structure 41. An appropriate4-(1H-benzimidazol-2-yl)[1,4]diazepanes of structure 3 is one asdescribed in Reaction Scheme A.1

In Reaction Scheme A.3, step 3, a protected compound of formula 41 isdeprotected to give a compound of structure 42. Deprotection reactions,such as the removal of amine protecting groups such as those describedin Protecting Groups in Organic Synthesis by T. Greene are well knownand appreciated in the art.

In Reaction Scheme A.3, step 4, a compound of structure 42 is aroylatedor alkylated to give a compound of formula (1) or a protected compoundof formula (1) in which G₁ and G₃ are —CH₂—. An aroylation is carriedout as described in Reaction Scheme B, optional step 7, above. Analkylation reaction is carried out as described in Reaction Scheme B,optional step 8, above, and can be carried out by reductive amination,such as described n Reaction Scheme A.2, step 2. Aroylations andalkylations of amines are well known and appreciated in the art.

In Reaction Scheme A.3, optional step 5, a compound of formula (1) or aprotected compound of formula (1) in which R₅ is hydrogen can bemodified to give a compound of formula (1) or a protected compound offormula (1) in which R₅ is not hydrogen and/or a protected compound offormula (1) is deprotected to give a compound of formula (1), asdescribed in Reaction Scheme A.1, optional step 3.

Reaction Scheme B is a general scheme for preparing alcohols ofstructure 2 in which G₃ is —CH₂— used as a starting material in ReactionSchemes A.1 and A.2 and for preparing amine of structure 11 used asstarting material in Reaction Scheme A.3. The reagents and startingmaterials are readily available to one of ordinary skill in the art. InReaction Scheme B, all substituents, unless otherwise indicated, are aspreviously defined.

In Reaction Scheme B, step 1, an appropriate nitrile of structure 5 isalkylated with an appropriate protected alcohol of structure 4 to givean ω-protected-hydroxyalkyl-nitrile of structure 6.

An appropriate nitrile of structure 5 is one in which r and Ar₁ are asdesired in the final product of formula (1) or Ar₁ gives rise afterdeprotection to an Ar₁ as desired in the final product of formula (1).An appropriate protected alcohol of structure 4 is one in which m is asdesired in the final product of formula (1) and the leaving group, L₂,is one which can be displaced by an anion derived from an appropriatenitrile of structure 5. Suitable leaving groups include but are notlimited to chloro, bromo, iodo, and mesylate with iodo and bromo beingpreferred. The selection and use of a suitable hydroxy protecting group,Pg₁, such as those described in Protecting Groups in Organic Synthesisby T. Greene are well known and appreciated in the art. The use oftetrahyropyran-2-yl and t-butyldimethylsilyl are generally preferred.

For example, the appropriate nitrile of structure 5 is contacted with1.0 to 1.2 molar equivalents of the appropriate protected alcohol ofstructure 4. The reaction is carried out in the presence of an equimolaramount of a suitable base, such as sodium hydride, sodiumbis-(trimethylsilyl)amide, potassium t-butoxide, and lithiumdiisopropylamide with sodium hydride and sodiumbis-(trimethylsilyl)amide being preferred. The reaction is carried outin a solvent, such as dimethylformamide or tetrahydrofuran. The reactionis generally carried out at temperatures of from −78° C. to 0° C.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme B, step 2, the ω-protected-hydroxyalkyl-nitrile ofstructure 6 is alkylated with ethyl bromoacetate or ethyl3-bromopropionate to give a nitrile ester compound of structure 7.

For example, the ω-protected-hydroxyalkyl-nitrile of structure 6 iscontacted with approximately a molar equivalent of ethyl bromqacetate orethyl bromopropionate. The reaction is carried out in the presence ofapproximately a molar equivalent of a suitable base, such as sodiumbis-(trimethylsilyl)amide or lithium diisopropylamide. The reaction iscarried out in a suitable solvent, such as tetrahydrofuran. The reactionis generally carried out at temperatures of from −78° C. to 0° C.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme B, step 3, the nitrile ester compound of structure 7is reduced and cyclized to give an oxo-3-(-protected-hydroxyalkyl)compound of structure 8. The cyclization may occur spontaneously afterthe reduction or may be carried out in a separate step after theisolation of the intermediate amine.

For example, the nitrile ester compound of structure 7 is contacted withan excess of an appropriate reducing agent, such as sodium borohydridein the presence of cobalt (II) chloride hexahydrate or hydrogen in thepresence of a suitable catalyst, such as Raney nickel or platinum oxide.For compounds of structure 7 in which Ar₁ is thienyl, sodium borohydridein the presence of cobalt (II) chloride hexahydrate is preferred.

When sodium borohydride in the presence of cobalt chloride is used, thereaction is carried out in a suitable solvent, such as methanol, orethanol. The reaction is generally carried out at temperatures of from0° C. to 50° C. Generally, the reactions require 1 to 72 hours.Generally, the cyclization occurs spontaneously under these conditions.The product can be isolated and purified by techniques well known in theart, such as extraction with aqueous acid, evaporation, trituration,chromatography, and recrystallization.

When Raney nickel is used, the reaction is carried out in a suitablesolvent containing ammonia, such as ethanol/aqueous ammonium hydroxideor methanol/aqueous ammonium hydroxide. The reaction is generallycarried out at temperatures of from ambient temperature to 70° C. Thereaction is carried out with hydrogen at pressures of from 15 psi to 120psi in an apparatus designed for carrying out reactions under pressure,such as a Parr hydrogenation apparatus. Generally, the cyclizationoccurs spontaneously under these conditions. The product can be isolatedby carefully removing the catalyst by filtration and evaporation. Theproduct can be purified by extraction, evaporation, trituration,chromatography, and recrystallization.

When platinum oxide is used, the reaction is carried out in a suitablesolvent such as ethanol, methanol, chloroform, ethanol/chloroformmixtures, or methanol/chloroform mixtures. The reaction is generallycarried out at temperatures of from ambient temperature to 50° C. Thereaction is carried out with hydrogen at pressures of from 15 psi to 120psi in an apparatus designed for carrying out reactions under pressure,such as a Parr hydrogenation apparatus. Generally, an amine intermediateis obtained under these conditions and is isolated by carefully removingthe catalyst by filtration and evaporation. The amine intermediate iscyclized by heating in a suitable solvent, such as ethanol, methanol,toluene, or chlorobenzene. The reaction is generally carried out attemperatures of from 50° C. to the refluxing temperature of the solvent.Generally, the reaction requires 8 to 48 hours. The product can bepurified by extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme B, optional step 4, theoxo-3-(-protected-hydroxyalkyl) compound of structure 8 is alkylatedwith an appropriate alkylating agent, X—CH₂—(CH₂)_(n)—Ar₂, to an1-arylaklyl-oxo compound of structure 9. An appropriate alkylatingagent, X—CH₂—(CH₂)_(n)—Ar₂, is one in which X is methanesulfonyl,chloro, bromo, or iodo; n is as desired in the final product of formula(1), and Ar₂ is as desired in formula (1) or gives rise afterdeprotection to Ar₂ as desired in formula (1).

For example, the oxo-3-(ω-protected-hydroxyalkyl) compound of structure8 is contacted with from 1 to 5 molar equivalents of an appropriatealkylating agent, X—CH₂—(CH₂)_(n)—Ar₂. The reaction is carried out in asuitable solvent, such as tetrahydrofuran, dimethyl sulfoxide, ordimethylformamide. The reaction is carried out in the presence of abase, such as sodium hydride, potassium t-butoxide, potassiumbis(trimethylsilyl)amide, or lithium diisopropylamide with sodiumhydride and potassium bis(trimethylsilyl)amide being preferred. Thereaction is generally carried out at temperatures of from 0° C. to 50°C. Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme B, step 6, the1-aryLalkyl-oxo-3-(ω-protected-hydroxyalkyl) compound of structure 9 isdeprotected to give an alcohol of structure 2 in which G₁ is —C(O)—. Adeprotection reaction, such as the removal of hydroxy protecting groupsutilizing suitable protecting groups such as those described inProtecting Groups in Organic Synthesis by T. Greene is well known andappreciated in the art.

In Reaction Scheme B, optional step 5, theoxo-3-(ω-protected-hydroxyalkyl) compound of structure 8 is reduced togive a 3-(ω-protected-hydroxyalkyl) compound of structure 11.

For example, the oxo-3-(ω-protected-hydroxyalkyl) compound of structure8 is contacted with an excess of a suitable reducing agent, such aslithium aluminum hydride, aluminum hydride, or borane dimethyl sulfidecomplex. The reaction is carried out in a suitable solvent, such astetrahydrofuran, diethyl ether, tetrahydrofuran/diethyl ether mixtures,or tetrahydrofuran/methyl t-butyl ether mixtures. The reaction isgenerally carried out at temperatures of from 0° C. to the refluxingtemperature of the solvent. Generally, the reactions require 1 to 72hours. The product can be isolated and purified by techniques well knownin the art, such as quenching of borane or aluminum complexes,extraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme B, optional step 7, the 3-(ω-protected-hydroxyalkyl)compound of structure 11 is aroylated with an appropriate aryl acid,aryl ester, aryl halide, aryl anhydride, or aryl mixed anhydride,A—C(O)—(CH₂)_(n)—Ar₂, to give an 1-aryl-3-(ω-protected-hydroxyalkyl)compound of structure 12. An appropriate aryl acid, aryl ester, aroylhalide, aryl anhydride, or aryl mixed anhydride, A—C(O)—(CH₂)_(n)—Ar₂,is one in which A is hydroxyl; an activated ester, such asO-hydroxysuccinimide, O-hydroxybenztriazole; an activated leaving group,such as chloro, bromo; or a group which forms an anhydride; or mixedanhydride, n is as desired in the final product of formula (1), and Ar₂is as desired in formula (1) or give rise after deprotection to Ar₂ asdesired in formula (1).

For example, the 3-(ω-protected-hydroxyalkyl) compound of structure 11is contacted with 1 to 1.5 molar equivalents of an appropriate arylacid, aryl ester, aryl halide, aroyl anhydride, or aryl mixed anhydride,A—C(O)—(CH₂)_(n)—Ar₂. The reaction is carried out in a suitable solvent,such as dichloromethane, tetrahydrofuran, acetonitrile,dimethylformamide, or pyridine. The reaction is carried out in thepresence of a base, such as sodium carbonate, sodium bicarbonate,triethylamine, N-methylmorpholine, diisopropylethylamine, or pyridine.The reaction is generally carried out at temperatures of from −20° C. to50° C. Generally, the reactions require 1 to 6 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme B, optional step 8, the 3-(ω-protected-hydroxyalkyl)compound of structure 11 is alkylated with an appropriate alkyl halide,X₃—CH₂—(CH₂)_(n)—Ar₂, to give an1-arylalkyl-3-(ω-protected-hydroxyalkyl) compound of structure 13. Anappropriate alkyl halide, X₃—CH₂—(CH₂)_(n)—Ar₂, is one in which X₃ ischloro or bromo, n is as desired in the final product of formula (1),and Ar₂ is as desired in formula (1) or gives rise after deprotection toAr₂ as desired in formula (1).

For example, the 3-(ω-protected-hydroxyalkyl) compound of structure 11is contacted with from 1.0 to 1.2 molar equivalents of an appropriatealkyl halide, X₃—CH₂—(CH₂)_(n)—Ar₂. The reaction is carried out in asuitable solvent, such as tetrahydrofuran, dimethyl sulfoxide,acetonitrile, tetrahydrofuran/water, toluene, toluene/water, ordimethylformamide. The reaction is carried out in the presence of abase, such as sodium carbonate, sodium bicarbonate, potassium carbonate,triethylamine, diisopropylethylamine, or pyridine. The reaction isgenerally carried out at temperatures of from 0° C. to refluxtemperature of the solvent. Generally, the reactions require 1 to 72hours. The product can be isolated and purified by techniques well knownin the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

In Reaction Scheme B, step 9, the1-arylaklyl-3-(ω-protected-hydroxyalkyl) compound of structure 13 isdeprotected to give an alcohol of structure 2 in which G₁, G₂, and G₃are —CH₂—. A deprotection reaction, such as the removal of hydroxyprotecting groups utilizing suitable protecting groups such as thosedescribed in Protecting Groups in Organic Synthesis by T. Greene is wellknown and appreciated in the art.

In Reaction Scheme B, step 10, the 1-aryl-3-(ω-protected-hydroxyalkyl)compound of structure 12 is deprotected to give an an alcohol ofstructure 2 in which G₁ is —CH₂—, G₂ is —C(O)—, and G₃ is —CH₂—.

Reaction Scheme C is a general scheme for preparing intermediates ofstructure 8 in which m is 2, r is 0, and q is 1 used in Reaction SchemeB to prepare alcohols of structure 2; and for preparing alcohols ofstructure 2 in which q is 1, r is 0, m is 2, and G₃ is —CH₂— used as astarting material in Reaction Schemes A.1 and A.2 and for preparingintermediates of structure 18 used as starting material in ReactionScheme A.3. The reagents and starting materials are readily available toone of ordinary skill in the art. In Reaction Scheme C, allsubstituents, unless otherwise indicated, are as previously defined.

In Reaction Scheme C, step 1, an appropriate aryl-acetonitrile ofstructure 5a is bis-alkylated with ethyl bromoacetate to give a nitrilebis-ester compound of structure 14. An appropriate aryl-acetonitrile ofstructure 5a is one in which Ar₁ is as desired in the final product offormula (1) or gives rise after deprotection to an Ar₁ as desired in thefinal product of formula (1).

For example, an appropriate aryl-acetonitrile of structure 5a iscontacted with 2.0 to 3.0 molar eauivalents of ethyl bromoacetate. Thereaction is carried out in the presence of approximately 2.0 to 3.0molar equivalents of a suitable base, such as sodiumbis(trimethylsilyl)amide or lithium diisopropylamide. The reaction iscarried out in a suitable solvent, such as tetrahydrofuran. The reactionis generally carried out at temperatures of from −78° C. to 0° C.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, distillation, chromatography, andrecrystallization.

In Reaction Scheme C, step 2, the nitrile bis-ester compound ofstructure 14 is reduced and cyclized to give a 5-oxo-3-acetic acid esterpyrrolidine of structure 15.

For example, the nitrile bis-ester compound of structure 14 is contactedwith a suitable reducing agent, such as sodium borohydride in thepresence of cobalt II chloride hexahydrate or hydrogen in the presenceof a suitable catalyst, such as Raney nickel or platinum oxide as taughtin Reaction Scheme B, step 3. For compounds of structure 14 in which Ar₁is thienyl, sodium borohydride in the presence of cobalt II chloridehexahydrate is preferred.

In Reaction Scheme C, optional step 3, the 5-oxo-3-acetic acid esterpyrrolidine of structure 15 is hydrolyzed to give a 5-oxo-3-acetic acidpyrrolidixie of structure 16.

For example, the 5-oxo-3-acetic acid ester pyrrolidine of structure 15is contacted with a suitable hydrolyzing agent, such as sodiumhydroxide, potassium hydroxide, or lithium hydroxide. The reaction iscarried out in a suitable solvent such as water, tetrahydrofuran/watermixtures, methanol, methanol/water mixtures, or ethanol/water mixtures.The reaction is generally carried out at temperatures of from 0° C. tothe refluxing temperature of the solvent. Generally, the reactionsrequire 1 to 72 hours. The product can be isolated and purified bytechniques well known in the art, such as extraction, evaporation,trituration, chromatography, and recrystallization.

In Reaction Scheme C, step 4, the 5-oxo-3-acetic acid pyrrolidine ofstructure 16 is reduced to give a 5-oxo-3-(2-hydroxyethyl)pyrrolidine ofstructure 17.

For example, the 5-oxo-3-acetic acid pyrrolidine of structure 16 iscontacted with a suitable borane reagent, such as borane dimethylsulfide complex. The reaction is carried out in a suitable solvent, suchas tetrahydrofuran. The reaction is generally carried out at atemperature of from 0° C. to the refluxing temperature of the solvent.When complete, the reaction is quenched by the careful addition of asuitable aqueous acid solution, such as 1 M hydrochloric acid solution.The product can be isolated and purified by techniques well known in theart, such as extraction, evaporation, trituration, chromatography, andrecrystallization.

Alternately, the 5-oxo-3-acetic acid pyrrolidine of structure 16 can bereduced by formation of a mixed anhydride intermediate and contactingthe mixed anhydride intermediate with a suitable mild reducing agent,such as sodium borohydride.

For example, the 5-oxo-3-acetic acid pyrrolidine of structure 16 iscontacted with 1.2 to 1.7 equivalents of a suitable base, such asN-methylmorpholine, in a suitable solvent, such as tetrahydrofuran ordiethyl ether. The reaction mixture is cooled to a temperature ofbetween −50° C. and 0° C. with −25° C. to −20° C. being preferred,before the addition of 1.2 to 1.7 equivalents of isobutyl chloroformate.The reaction is allowed to stir for 30 minutes to 3 hours to allow forthe formation of the mixed anhydride. After the formation of the mixedanhydride is complete, sodium borohydride is added. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, chromatography, and recrystallization.

In Reaction Scheme C, step 5, the 5-oxo-3-(2-hydroxyethyl)-pyrrolidineof structure 17 is protected to give a5-oxo-3-(ω-protected-hydroxyethyl)pyrrolidine of structure 8 in which mis 2, r is 0, and q is 1 used in Reaction Scheme B for preparingcompounds of structure 2. The selection and use of suitable protectinggroups such as those described in Protecting Groups in Organic Synthesisby T. Greene is well known and appreciated in the art.

In Reaction Scheme C optional step 6, the 5-oxo-3-acetic acid esterpyrrolidine of structure 15 is reduced to give a3-(ω-hydroxyethyl)-pyrrolidine of structure 18 as taught in ReactionScheme B, optional step 5.

In Reaction Scheme C, step 7, the 3-(ωhydroxyethyl) pyrrolidine ofstructure 18 is aroylated with an appropriate aroyl halide, arylanhydride, or aryl mixed anhydride, A₁—C(O)—(CH₂)_(n)—Ar₂, to give analcohol of structure 2. An appropriate aroyl halide, aryl anhydride, oraryl mixed anhydride, A₁—C(O)—(CH₂)_(n)—Ar₂, is one in which A₁ is anactivated leaving group, such as chloro, bromo, or a group which formsan anhydride or mixed anhydride, n is as desired in the final product offormula (1), and Ar₂ is as desired in formula (1) or gives rise afterdeprotection to Ar₂ as desired in formula (1).

For example, the 3-(ω-hydroxyethyl)pyrrolidine of structure 18 iscontacted with 1 to 1.1 molar equivalents of an appropriate aroylhalide, aryl anhydride, or aryl mixed anhydride, A₁—C(O)—(CH₂)_(n)—Ar₂.The reaction is carried out in a suitable solvent, such astetrahydrofuran, dichloromethane, acetone, ethyl acetate, or diethylether. The reaction is carried out in the presence of a base, such asN-methylmorpholine, sodium carbonate, triethylamine,diisopropylethylamine, potassium carbonate or sodium bicarbonate. Thereaction is generally carried out at temperatures of from −78° C. toambient temperature. Generally, the reactions require 1 to 24 hours. Theproduct can be isolated and purified by techniques well known in theart, such as extraction, evaporation, trituration, chromatography, andrecrystallization.

Alternately, for example, the 3-(ω-hydroxyethyl) pyrrolidine ofstructure 18 is contacted with 1 to 1.1 molar equivalents of anappropriate aroyl halide, arylanhydride, or aryl mixed anhydride,A₁—C(O)—(CH₂)_(n)—Ar₂ under Schotten-Baumann conditions. The reaction iscarried out in a suitable solvent mixture, such as acetone/water,tetrahydrofuran/water, or ethyl acetate/water. The reaction is carriedout in the presence of a base, such as potassium carbonate, potassiumbicarbonate, sodium bicarbonate, or sodium carbonate. The reaction isgenerally carried out at temperatures of from −20° C. to 50° C.Generally, the reactions require 15 minutes to 24 hours. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme C, optional step 8 the 5-oxo-3-acetic acid esterpyrrolidine of structure 15 is alkylated with an appropriate alkylhalide, X₄—CH₂—(CH₂)_(n)—Ar₂, to give an 1-arylalkyl-5-oxo-3-acetic acidester pyrrolidine of structure 19. An appropriate alkyl halide,X₄—CH₂—(CH₂)_(n)—Ar₂, is one in which X₄ is chloro, bromo, or iodo; n isas desired in the final product of formula (1), and Ar₂ is as desired informula (1) or gives rise after deprotection to Ar₂ as desired informula (1).

For example, the 5-oxo-3-acetic acid ester pyrrolidine of structure 15is contacted with from 1.0 to 1.2 molar equivalents of an appropriatealkyl halide, X₄—CH₂—(CH₂)_(n)—Ar₂. The reaction is carried out in asuitable solvent, such as tetrahydrofuran, dimethyl sulfoxide,acetonitrile, or dimethylformamide. The reaction is carried out in thepresence of a base, such as sodium hydride, sodiumbis(trimethylsilyl)amide, potassium t-butoxide. The reaction isgenerally carried out at temperatures of from 0° C. to 50° C. Generally,the reactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme C, step 9, the 1-arylalkyl-5-oxo-3-acetic acid esterpyrrolidine of structure 19 is hydrolyzed to give an1-arylalkyl-5-oxo-3-acetic acid pyrrolidine of structure 20.

For example, the 1-arylalkyl-5-oxo-3-acetic acid ester pyrrolidine ofstructure 19 is contacted with a suitable hydrolyzing agent, such assodium hydroxide, potassium hydroxide, or lithium hydroxide. Thereaction is carried out in a suitable solvent such as water,tetrahydrofuran/water mixtures, methanol, methanol/water mixtures, orethanol/water mixtures. The reaction is generally carried out attemperatures of from 0°C. to the refluxing temperature of the solvent.Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme C, step 10, the 1-arylalkyl-5-oxo-3-acetic acidpyrrolidine of structure 20 is reduced as taught in Reaction Scheme C,step 4, above, to give an alcohol of structure 2 in which r is 0, q is1, m is 2, G₁ is —C(O)—, and G₂ and G₃ are —CH₂—.

Reaction Scheme D sets forth a synthetic procedure for preparingalcohols of structure 2 in which G₁ is —CH₂— used as a starting materialin Reaction Scheme A.1 and A.2. The reagents and starting materials usedin Reaction Scheme D are readily available to one of ordinary skill inthe art. In Reaction Scheme D, all substituents, unless otherwiseindicated, are as previously defined.

In Reaction Scheme D, step 1, an appropriate compound of structure 21 isalkylated with an appropriate alkylating agent to give an1-arylalkyl-2-oxo compound of structure 22. An appropriate compound ofstructure 21 is one in which q is as desired in formula (1). Anappropriate alkylating agent, X—CH₂—(CH₂)_(n)—Ar₂, is as defined inReaction Scheme B, optional step 4.

For example, an appropriate compound of structure 21 is contacted withfrom 1 to 5 molar equivalents of an appropriate alkylating agent,X—CH₂—(CH₂)_(n)Ar₂. The reaction is carried out in a suitable solvent,such as tetrahydrofuran. The reaction is carried out in the presence ofa base, such as sodium hydride, potassium t-butoxide, potassiumbis(trimethylsilyl)amide with potassium bis(trimethylsilyl)amide beingpreferred. The reaction is generally carried out at temperatures of from−78° C. to the refluxing temperature of the solvent. Generally, thereactions require 1 to 72 hours. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, trituration, chromatography, and recrystallization.

In Reaction Scheme D, step 2, the 1-arylalkyl-2-oxo compound ofstructure 22 is arylmethylated with an appropriate arylmethylating agentto give a 1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23. Anappropriate arylmethylating agent, X₅—CH₂—Ar₁, is one in which X₅ ismethanesulfonyl, chloro, bromo, or iodo and Ar₁ is as desired in formula(1) or gives rise after deprotection to Ar₁ as desired in formula (1).Examples of appropriate arylmethylating agents include, but are notlimited to benzyl bromide, benzyl chloride, 3,4,5-trimethoxybenzylmethanesulfonate, 4-fluorobenzyl bromide, 4-fluorobenzyl chloride,3,4-difluorobenzyl bromide, 3,4-difluorobenzyl chloride, 4-methoxybenzylchloride, 3,4-dimethoxybenzyl bromide, 3,4-dimethoxybenzyl chloride,3,4-dichlorobenzyl bromide, 3,4-dichlorobenzyl chloride, 3-chlorobenzylbromide, 4-chlorobenzyl chloride, 2,4-difluorobenzyl bromide,2,4-difluorobenzyl chloride, 2-(bromomethyl)thiophene,2-(chloromethyl)pyridine, 3-(chloromethyl)pyridine,4-(chloromethyl)pyridine, 1-(chloromethyl)naphthlene,2-(chloromethyl)naphthlene, and the like.

For example, the 1-arylalkyl-2-oxo compound of structure 22 is contactedwith from 1 to 5 molar equivalents of an appropriate arylmethylatingagent. The reaction is carried out in a suitable solvent, such astetrahydrofuran. The reaction is carried out in the presence of a base,such as sec-butyl lithium, n-butyl lithium, and lithiumbis(trimethylsilyl)amide. The reaction is generally carried out attemperatures of from 0° C. to −78° C. Generally, the reactions require 1to 72 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, trituration,chromatography, and recrystallization.

In Reaction Scheme D, step 3, the 1-arylalkyl-2-oxo-3-arylmethylcompound of structure 23 is alkylated with an appropriate protectedalcohol, Pg2O—(CH₂)_(m)—L₃, to give an1-arylalkyl-2-oxo-3-arylmethyl-3-(-protected-hydroxyalkyl) compound ofstructure 24.

An appropriate protected alcohol, Pg₂O—(CH₂))_(m)—L₃, is one in which mis as desired in the final product of formula (1) and the leaving group,L₃, is one which can be displaced by an anion derived from anappropriate 1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23.Suitable leaving groups, L₃, include but are not limited tomethanesulfonyl, chloro, bromo, and iodo. Suitable hydroxy protectinggroups such as those described in Protecting Groups in Organic Synthesisby T. Greene are well known and appreciated in the art. In ReactionScheme D, the use of t-butyldimethylsilyl is generally preferred.

For example, the 1-arylalkyl-2-oxo-3-arylmethyl compound of structure 23is contacted with 1.0 to 1.2 molar equivalents of an appropriateprotected alcohol, Pg₂O-(CH₂)_(m)—L₃. The reaction is carried out in thepresence of an equimolar amount of a suitable base, such as sec-butyllithium, n-butyl lithium, and lithium bis(trimethylsilyl)amide. Thereaction is carried out in a solvent, such as tetrahydrofuran. Thereaction is generally carried out at temperatures of from −78° C. to 0°C. Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme D, step 4, the1-arylalkyl-2-oxo-3-arylmethyl-3-(-protected-hydroxyalkyl) compound ofstructure 24 is deprotected to give an alcohol of structure 2 in which ris 1 and G₃ is —C(O)—. A deprotection reaction, such as the removal ofhydroxy protecting groups utilizing suitable protecting groups such asthose described in Protecting Groups in Organic Synthesis by T. Greeneis well known and appreciated in the art.

In Reaction Scheme D, optional step 5, the1-arylalkyl-2-oxo-3-arylmethyl-3-(-protected-hydroxyalkyl) compound ofstructure 24 is reduced to give an1-arylalkyl-3-arylmethyl-3-(-protected-hydroxyalkyl) compound ofstructure 25.

This reaction is carried out as taught in reaction Scheme B, optionalstep 5 and may result in the removal of the protecting group Pg₂. Whenthe protection group Pg₂ is removed the same or another protecting groupPg₂ may be introduced or, alternately, the steps that follow may becarried out on the unprotected hydroxy compound.

In Reaction Scheme D, step 6, an appropriate1-arylalkyl-3-arylmethyl-3-(-protected-hydroxyalkyl) compound ofstructure 25 is debenzylated to give a3-arylmethyl-3-(ω-protected-hydroxyalkyl) compound of structure 26. Anappropriate 1-arylalkyl-3-arylmethyl-3-(ω-protected-hydiroxyalkyl)compound of structure 25 is one in which n is 0 and Ar₂ is phenyl or4-methoxyphenyl; and m, q, and Ar₁ are as desired in the final productof formula (l) or Ar₁ gives rise after deprotection to an Ar₁ as desiredin the final product of formula (1).

For example, and an appropriate1-arylalkyl-3-arylmethyl-3-(ω-protected-hydroxyalkyl) compound ofstructure 25 is hydrogenated. The reaction is carried out in a suitablesolvent, such as ethanol, methanol, or water. The reaction is carriedout in the presence of a suitable catalyst, such as 20% palladiumhydroxide-on-carbon. The reaction is carried out at pressures of fromatmospheric pressure to about 100 psi. When the reaction is carried outat a pressure greater than atmospheric pressure, the reaction is carriedout in a suitable pressure apparatus, such as a Parr apparatus or anautoclave. The reaction is generally carried out at temperatures of from50° C. to 0° C. Generally, the reactions require 1 to 72 hours. Theproduct can be isolated and purified by techniques well known in theart, such as filtration, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme D, step 7, the3-arylmethyl-3-(ω-protected-hydroxyalkyl) compound of structure 26 isaroylated as taught in Reaction Scheme B, optional step 7 to give an1-aroyl-3-arylmethyl-3-(ω-protected-hydroxyalkyl) compound of structure27.

In Reaction Scheme D, step 8, the1-aroyl-3-arylmethyl-3-(ω-protected-hydroxyalkyl) compound of structure27 is deprotected, if required, to give an alcohol of structure 2 inwhich r is 1, G₃ is —CH₂—, and G₂ is —C(O)—. A deprotection reaction,such as the removal of hydroxy protecting groups utilizing suitableprotecting groups such as those described in Protecting Groups inOrganic Synthesis by T. Greene is well known and appreciated in the art.

Reaction Scheme E sets forth the preparation of alcohols of structure 2in which r is 0 and G₁ is —CH₂— used as a starting material in ReactionScheme A.1 and A.2. The reagents and starting materials are readilyavailable to one of ordinary skill in the art. In Reaction Scheme E, allsubstituents, unless otherwise indicated, are as previously defined.

In Reaction Scheme E, step 1, an appropriate methyl arylacetate ofstructure 28 is alkylated with an appropriate ω-cyano alkylating agentof structure 29 to give a cyano ester of structure 30.

An appropriate methyl arylacetate of structure 28 is one in which Ar₁ isas desired in formula (1) or gives rise after deprotection to Ar₁ asdesired in formula (1). An appropriate ω-cyano alkylating agent ofstructure 29 is one in which q is as desired in formula (1) and L₄ ischloro or bromo. Examples of appropriate ω-cyano alkylating agents ofstructure 29 include α-chloroacetonitrile, α-bromoacetonitrile,acrylonitrile, β-chloropropionitrile, and β-bromopropionitrile.

For example, an appropriate methyl arylacetate of structure 28 iscontacted with from 0.8 to 1.2 molar equivalents of an appropriateω-cyano alkylating agent of structure 29. The reaction is carried out ina suitable solvent, such as tetrahydrofuran. The reaction is carried outin the presence of a base, such as sodium hydride, lithiumbis(trimethylsilyl)amide, or potassium bis(trimethylsilyl)amide. Thereaction is generally carried out at temperatures of from 0° C. to −78°C. Generally, the reactions require 1 to 72 hours. The product can beisolated and purified by techniques well known in the art, such asextraction, evaporation, trituration, chromatography, andrecrystallization.

In Reaction Scheme E, step 2, the cyano ester of structure 30 is reducedand cyclized to give a 2-oxo-3-aryl compound of structure 31 as taughtin Reaction Scheme B, step 3.

In Reaction Scheme E, step 3, the 2-oxo-3-aryl compound of structure 31is alkylated with an appropriate alkylating agent as taught in ReactionScheme D, step 1, to give an 1-arylalkyl-2-oxo-3-aryl compound ofstructure 32.

In Reaction Scheme E, step 4, the 1-arylalkyl-2-oxo-3-aryl compound ofstructure 32 is alkylated with an appropriate protected alcohol,Pg₂O—(CH₂)_(m)—L₃, as taught in Reaction Scheme D, step 3, to give a3-(ω-protected-hydroxyalkyl)-1-arylalkyl-2-oxo-3-aryl compound ofstructure 33.

In Reaction Scheme E, step 5, the3-(ω-protected-hydroxyalkyl)-1-arylalkyl-2-oxo-3-aryl compound ofstructure 33 is deprotected to give an alcohol of structure 2 in which ris 0 and G₃ is —C(O)—. A deprotection reaction, such as the removal ofhydroxy protecting groups utilizing suitable protecting groups such asthose described in Protecting Groups in Organic Synthesis by T. Greeneis well known and appreciated in the art.

In Reaction Scheme E, optional step 6, the3-(ω-protected-hydroxyalkyl)-1-arylalkyl-2-oxo-3-aryl compound ofstructure 33 is reduced to give a3-(ω-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of structure34.

This reaction is carried out as taught in reaction Scheme 3, optionalstep 5 and may result in the removal of the protecting group Pg₂. Whenthe protection group Pg₂ is removed the same or another protecting groupPg₂ may be introduced or, alternately, the steps that follow may becarried out on the unprotected hydroxy compound.

In Reaction Scheme E, step 7, an appropriate3-(ω-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound of structure 34is debenzylated as taught in Reaction Scheme D, step 6, to give a3-(ω-protected-hydroxyalkyl)-3-aryl compound of structure 35. Anappropriate 3-(ω-protected-hydroxyalkyl)-1-arylalkyl-3-aryl compound ofstructure 34 is one in which n is 0 and Ar₂ is phenyl or4-methoxyphenyl; and m, q, and Ar₁ are as desired in the final productof formula (1) or Ar₁ gives rise after deprotection to an Ar₁ as desiredin the final product of formula (1).

In Reaction Scheme E, step 8, a 3-(ω-protected-hydroxyalkyl)-3-arylcompound of structure 35 is aroylated as taught in Reaction Scheme B,optional step 7 to give an 1-aroyl-3-(ω-protected-hydroxyalkyl)-3-arylcompound of structure 36.

In Reaction Scheme E, step 9, the1-aroyl-3-(ω-protected-hydroxyalkyl)-3-aryl compound of structure 36 isdeprotected, if required, to give an alcohol of structure 2 in which ris 0, G₃ is —CH₂—, and G₂ is —C(O)—. A deprotection reaction, such asthe removal of hydroxy protecting groups utilizing suitable protectinggroups such as those described in Protecting Groups in Organic Synthesisby T. Greene is well known and appreciated in the art.

The following examples and preparations present typical syntheses of thecompounds of formula (1). These examples are understood to beillustrative only and are not intended to limit the scope of theinvention in any way.

PREPARATION 1.1

4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane

According to the method of R. Iemura et al., J. Med. Chem., 29 1178-1183(1986), combine 1-chloro-2-nitrobenzene (69.0 g, 440 mmol) and2-aminoethyl ethyl ether (102.5 g, 1.15 mol) and heat to reflux. After18 hours, cool and dilute the reaction mixture with ethyl acetate (400mL). Extract with brine. Dry the organic layer over Na₂SO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with dichloromethane to giveN-(2-ethoxyethyl)-2-nitroaniline.

Combine N-(2-ethoxyethyl)-2-nitroaniline (85.4 g, 406 mmol) and ethanol(300 mL). Add a solution of sodium hydroxide (6 g) in water (60 mL).Heat to reflux. Remove the heating and add portionwise zinc metal (106g, 1.62 mol) at a rate such that the reaction is maintained at reflux.After the addition of zinc metal is complete stir for 30 minutes. Filterthe reaction mixture and rinse with water. Extract the filtrate threetimes with ethyl acetate. Dry the combined organic layers over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with ethyl acetate to give1-(2-ethoxyethyl)-1,2-phenylenediamine.

Combine 1-(2-ethoxyethyl)-1,2-phenylenediamine (55.4 g, 307 mmol) andurea (37.5 g, 624 mmol). Heat at 150° C. After 5 hour, cool to ambienttemperature and stir. After 18 hours, partition the reaction mixturebetween ethyl acetate and water. Separate the layers and extract theaqueous layer three times with ethyl acetate. Combine the organic layersand extract with aqueous 1 M hydrochloric acid solution. Dry the organiclayer over Na₂SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with dichloromethane togive the 2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole.

Combine 2-hydroxy-1-(2-ethoxyethyl)-1H-benzimidazole (36.4 g, 177 mmol)and phosphorous oxychloride (72 mL) and reflux. After 30 minutes, coolto ambient temperature and pour the reaction mixture onto crushed ice.Adjust the pH to about 9 using aqueous 50% sodium hydroxide solution.Extract three times with ethyl acetate. Combine the organic layers andextract with brine. Dry the organic layer over Na₂SO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with ethyl acetate to give the2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole.

Combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (12.2 g, 54.2 mmol)and [1,4]diazepane (11.34 g, 113 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (9 mL), and pyridine (90 mL). Heat toreflux. After 18 hours, cool to ambient temperature and evaporate invacuo to give a residue. Partition the residue between aqueous 1 Msodium hydroxide solution and ethyl acetate. Separate the layers andextract the aqueous layer two times with ethyl acetate. Combine theorganic layers, dry over Na₂SO₄, filter, and evaporate in vacuo to givea residue. Chromatograph the residue on silica gel eluting sequentiallywith 30% methanol/ethyl acetate and then 2% concentrated aqueousammonia/methanol to give the title compound: R_(f)=0.26 (silica gel, 2%concentrated aqueous ammonia/methanol).

Alternately, combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (15.56g, 69.3 mmol) and [1,4]diazepane (13.89 g, 138.7 mmol),1,8-diazabicyclo[5.4.0]undec-7-ene (12.34 mL, 83.1 minol), and pyridine(200 mL). Heat to reflux. After 18 hours, cool to ambient temperatureand evaporate in vacuo to give a residue. Partition the residue betweenaqueous 1 M sodium hydroxide solution and dichloromethane. Separate thelayers and extract the aqueous layer two times with dichloromethane.Combine the organic layers, extract with aqueous 1 M sodium hydroxidesolution, water, and then brine. Dry the organic layer over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 2% concentrated aqueousammonia/methanol to give the title compound: R_(f)=0.26 (silica gel, 2%concentrated aqueous ammonia/methanol).

PREPARATION 1.2

4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane

Combine 2-chloro-1H-benzimidazole (21.1.4 g, 138.4 mmol) anddimethylformamide (200 mL). Add portionwise, sodium hydride (24.0 g, 60%in oil, 153.3 mmol). After 15 minutes, add 2-chloroethyl ethyl ether(21.9 g, 201,5 mmol). Heat to 60° C. After 18 hours, cool the reactionmixture and dilute with ethyl acetate. Extract with a saturated aqueoussodium bicarbonate solution, water, and then brine. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially with 10%ethyl acetate/hexane and then 30% ethyl acetate hexane to give the2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole: R_(f)=0.74 (silica gel, 7/3ethyl acetate/hexane).

Combine 2-chloro-1-(2-ethoxyethyl)-1H-benzimidazole (22.3 g, 99.4 mmoL),1-methyl[1,4]diazepane (19 mL, 152.8 mmol), and triethylamine (75 mL).Heat to 70° C. After 18 hours, add 1-methyl[1,4]diazepane (10 mL) andcontinue to heat at reflux. After 96 hours, cool to ambient temperatureand partition the reaction mixture between water and ethyl acetate.Separate the layers and extract the organic layer with a saturatedaqueous sodium bicarbonate solution and then brine. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially with 50%ethyl acetate/hexane and then 10% methanol/dichloromethane to give1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.52 (silica gel, dichloromethane/methanol/concentrated aqueousammonia, 90/10/0.1).

Combine1-methyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.79g, 5.9 mmol) and ethyl chloroformate (0.75 mL, 7.8 mmol) in toluene (20mL). Heat to 80° C. After 2 hours, cool the reaction mixture and dilutewith ethyl acetate. Extract with a saturated aqueous sodium bicarbonatesolution, dry the organic layer over MgSO₄, filter, and evaporate invacuo to give1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.87 (silica gel, dichloromethane/methanol, 90/10).

Combine1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and potassium hydroxide(40.7 g, 725 mmol) in ethylene glycol (150 mL). Heat to reflux. After 5hours, cool the reaction mixture and dilute with water (500 mL). Extractthree times with dichloromethane. Combine the dichloromethane layers andextract with a saturated aqueous sodium bicarbonate solution and thenbrine. Dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give the title compound: R_(f)=0.25 (silica gel,dichloromethane/methanol, 90/10).

PREPARATION 2

4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic AcidSalt

Combine 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.30g), 48% hydriodic acid (10 mL), ethanol (10 mL), and diethyl ether (80mL) and stir. After 30 minutes add diethyl ether, (800 mL) and continueto stir to give a solid. Collect the solid by filtration and dry invacuo to give the title compound: mp; 156-163° C.

Alternately, combine4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (18.42 g, 63.9mmol), 57% hydriodic acid (8.30 mL), ethanol (80 mL) and stir. After 2.5hours, cool to give a solid. Collect the solid by filtration, rinse withdiethyl ether, and dry in vacuo to give the title compound.

EXAMPLE 1

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine

1.1 Synthesis of 3-cyano-3-(3,4-dimethoxyphenyl)pentanedioic diethylester

Combine 3,4-dimethoxyphenylacetonitrile (20 g, 113 mmol) and anhydroustetrahydrofuran (100 mL). Cool in a dry-ice/acetone bath. Add dropwise asolution of sodium bis(trimethylsilyl)amide (226 mL, 1 M in THF, 226mmol). When the addition is complete warm the reaction mixture to 10° C.and allow to stir for 15 minutes. Cool in a dry-ice/acetone bath, adddropwise ethyl bromoacetate (37.7 g, 226 mmol). When the addition ofethyl bromoacetate is complete, warm the reaction mixture to ambienttemperature. After 18 hours, partition the reaction mixture betweendiethyl ether and water. Extract the organic layer with water andsaturated aqueous solution of ammonium chloride. Separate the organiclayer, dry over MgSO₄, filter, and concentrate inuacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 33% ethylacetate/hexane. Remove residual solvent in vacuo at 82° C. to give thetitle compound: R_(f)=0.37 (silica gel, 33% ethyl acetate/hexane).Elemental Analysis calculated for C₁₈H₂₃NO₆: C_(61.88;) H 6.64; N 4.01;Found: C_(61.79;) H 6.62; N 3.91.

1.2 Synthesis of (3-(3,4-dimethoxyphenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Combine 3-cyano-3-(3,4-dimethoxyphenyl)pentanedioic diethyl ester (1.3g, 3.24 mmol) and cobalt(II)chloride hexahydrate (1.54 g, 6.48 mmol) inmethanol (50 mL). While maintaining the temperature at or below 20° C.with an ice-bath, add portionwise sodium borohydride (2.17 g, 57 mmol).After the addition is complete, allow the reaction mixture to stand atambient temperature for 18 hours. Evaporate the reaction mixture invacuo to obtain a residue. Partition the residue between dichloromethaneand 1M hydrochloric acid solution. Extract the aqueous layer severaltimes with dichloromethane, combine the organic layers, dry over Na₂SO₄,filter, and concentrate in vacuo to obtain a residue. Chromatograph theresidue on silica gel eluting with 20/1 ethyl acetate/methanol. Removeresidual solvent: in vacuo at 82° C. to give the title compound:R_(f)=0.74 (silica gel, 5/1 ethyl acetate/methanol); mp; 116-118° C.Elemental Analysis calculated for C₁₆H₂₁NO₅: C, 62.53; H, 6.89; N, 4.56;Found: C, 62.52; H, 6.85; N, 4.50.

1.3 Synthesis of 3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine lithium aluminum hydride (0.99 g, 26.0 mmol) and anhydroustetrahydrofuran (20 mL). Slowly, add(3-(3,4-dimethoxyphenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester(2.0 g, 6.5 mmol) as a solution in anhydrous tetrahydrofuran (40 mL).After the addition is complete, heat to reflux. After 18 hours, cool inan ice-bath. Add water (1 mL) dropwise at such a rate that thetemperature of the reaction mixture does not rise above 20° C. Cool to10° C., add 15% sodium hydroxide solution (1.0 mL). Add water (3 mL).After 15 minutes, filter the reaction mixture and concentrate thefiltrate in vacuo to give the title compound: R_(f)=0.68 (silica gel,5/1 ethyl acetate/methanol).

Prepare an analytical sample as follows: Combine3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (0.51 g, 2.02mmol) and oxallic acid (0.18 g, 2.00 mmol) in tetrahydrofuran (70 mL).After 18 hours, filter and dry. Triturate with diethyl ether (100 mL),filter and dry in vacuo at 81° C. to give the title compound as itsoxalate salt: mp; 140-142° C. Elemental Analysis calculated forC₁₄H₂₁NO₃•C₂H₂O₄: C, 56.30; H, 6.79; N, 4.10; Found: C, 56.15; H, 6.76;N, 4.13.

1.4.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (2.27 g,9.03 mmol) and N-methylmorpholine (2.48 mL, 22.6 mmol) in anhydrousdichloromethane (100 mL). Cool the reaction mixture to −5° C. with ansalt-ice bath. Slowly, add 3,4,5-trimethoxybenzoyl chloride (2.2 g, 9.5mmol) as a solution in dichloromethane (30 mL). Warm to ambienttemperature. After 18 hours, extract the reaction mixture with asaturated solution of potassium carbonate. Dry the organic layer overNa₂SO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with 95%dichloromethane/methanol to obtain a residue. Combine the residue anddichloromethane (100 mL), and extract 3 times with 1M hydrochloric acidsolution and saturated solution of potassium carbonate. Dry the organiclayer over Na₂SO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with 20/1 ethylacetate/methanol to obtain an oil: R_(f)=0.14 (silica gel, 20/1 ethylacetate/methanol). Dry in vacuo at 110° C. to obtain the title compoundas a glass: mp; 60-62° C. Elemental Analysis calculated for C₂₄H₃₁NO₇:C, 64.70; H, 7.01; N, 3.14; Found C, 64.40; H, 7.21; N, 2.85.

1.4.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (5.34 g,21.2 mmol) and sodium carbonate (1.24 g, 11.7 mmol) in ethylacetate/water (4/1) (120 mL). Cool the reaction mixture to −5° C. withan salt-ice bath. Slowly, add 3,4,5-trimethoxybenzoyl chloride (5.14 g,22.3 mmol) as a solution in ethyl acetate (60 mL) at a rate such thatthe temperature of the reaction mixture does not rise above 0° C.Maintain the reaction temperature at about 0° C. After 18 hours,separate the organic layer. Extract the organic layer twice with 1 Maqueous hydrochloric acid solution, saturated solution of sodiumbicarbonate, water and a saturated solution of sodium chloride. Dry theorganic layer over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Combine the aqueous layers and neutralize with a saturatedsolution of sodium bicarbonate. Extract the neutralized aqueous layerswith dichloromethane. Dry the organic layer over Na₂SO₄, filter, andconcentrate in vacuo to obtain another residue. Combine the residues andchromatograph on silica gel eluting with 10/1 dichloromethane/methanolto obtain a residue. Combine the residue and dichloromethane (100 mL),and extract 3 times with 1M hydrochloric acid solution and saturatedsolution of potassium carbonate. Dry the organic layer over Na₂SO₄,filter, and concentrate in vacuo to obtain the title compound:R_(f)=0.23 (silica gel, 10/1 ethyl acetate/methanol).

1.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine(0.43 g, 0.97 mmol), triethylamine (3.3 mL, 2.4 mmol), and anhydrousdichloromethane (30 mL). Cool the reaction mixture to −5° C. with ansalt-ice bath. Slowly, add methanesulfonyl chloride (0.082 mL, 1.06mmol) at such a rate that the temperature of the reaction mixture doesnot rise above 2° C. Warm to ambient temperature. After 18 hours, quenchthe reaction by the addition of ice. Separate the organic layer andextract 3 times with 1M hydrochloric acid solution and 2 times with asaturated solution of sodium bicarbonate. Dry the organic layer overNa₂SO₄, filter, and concentrate in vacuo to obtain the title compound:R_(f)=0.48 (silica gel, 20/1 ethyl acetate/methanol).

1.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.86 g, 1.64 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.57 g, 1.97mmol), sodium iodide (0.25 g, 1.64 mmol), and N,N-diisopropylethylamine(0.42 g, 3.3 mmol) in acetonitrile (9 mL). Heat to reflux. After 3 days,cool and dilute the reaction mixture ethyl acetate. Extract three timeswith a saturated aqueous ammonium chloride solution, twice with asaturated aqueous sodium bicarbonate solution, and then brine. Dry theorganic layer over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/methanol to give, after drying in vacuo at 70° C., the titlecompound: mp; 45-50° C. Elemental Analysis calculated for C₄₀H₅₃N₅O₇•0.9H₂O: C, 65.56; H, 7.55; N, 9.56; Found: C, 65.57; H, 7.38; N, 9.63.

1.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidinefumaric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethoxyphenyl)pyrrolidine(0.29 g, 0.40 mmol), fumaric acid (0.14 g, 1.21 mmol), and ethyl acetate(100 mL). Heat to reflux. After 18 hours, cool to ambient temperatureand evaporate in vacuo to give a residue. Triturate the residue withdiethyl ether (100 mL) with stirring to give a solid. Collect the solidby filtration and dry in vacuo at 65° C. to give the title compound; mp;90-100° C. Elemental Analysis calculated for C₄₀H₅₃N₅O₇•2C₄H₄O₄•1.6 H₂O:C, 59.03; H, 6.62; N, 7.17; Found: C, 59.18; H, 6.43; N, 7.18.

EXAMPLE 2

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethyoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

2.1.1 Synthesis of 3-cyano-3-(3,4-dichlorophenyl)pentanedioic aciddiethyl ester

Prepare by the method of Example 1.1 using3,4-dichlorophenylacetonitrile (30.0 g, 0.161 mol). Purify byrecrystallization from diethyl ether to give the title compound:R_(f)=0.28 (silica gel, 20% ethyl acetate/hexane), mp; 68-69° C.Elemental Analysis calculated for C₁₆H₁₇C₁₂NO₄: C, 53.65; H, 4.78; N,3.91; Found: C, 53.69; H, 4.79; N, 3.93.

2.1.2 Synthesis of 3-cyano-3-(3,4-dichlorophenyl)pentanedioic aciddiethyl ester

Cool a solution of sodium bis(trimethylsilyl)amide (480 lb, 1 M in THF)to about −10° C. and stir. Add a solution of3,4-dichlorophenylacetonitrile in methyl t-butyl ether (34.5% by weight,125 lb of solution) at such a rate that the temperature of the reactionmixture does not rise above about 10° C. Combine ethyl bromoacetate (94lb) and methyl t-butyl ether (about 125 lb) and cool to about −18° C.and then add the solution prepared above over 60-90 minutes. After thereaction is complete, as determined by chromatography, add water (18gal). Add a 12 M aqueous hydrochloric acid solution until the pH isabout 4. If the pH falls below 3, use 20% aqueous sodium hydroxidesolution to raise the pH to about 4. Separate the layers and extract theorganic layer with brine. Evaporate in vacuo at about 40° C. to give aresidue. Combine the residue and isopropanol (about 45 lb) and evaporatein vacuo at about 40° C. to give a residue. Add isopropanol (190 lb),warm to about 35° C., and then cool to about −10° C. to give a solid.Collect the solid by filtration, rinse with cold isopropanol, andcentrifuge to give the title compound as a wet cake containingisopropanol.

2.2.1 Synthesis of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Prepare by the method of Example 1.2 using3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (10 g, 28mmol). Purify by chromatography on silica gel eluting sequentially with3% methanol/dichloromethane and then 6% methanol/dichloroinethane togive the title compound.

2.2.2 Synthesis of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester(32 g, 89 mmol) and ethanol (150 mL) in a Parr bottle. Add Raney nickel(100 g) and an aqueous concentrated ammonia solution (40 mL).Hydrogenate at 50 psi for 24 h. Filter through a celite pad and rinsethe solids with ethanol. Evaporate the filtrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 6%methanol/dichloromethane to give the title compound: R_(f)=0.34 (silicagel, 6% methanol/dichloromethane); mp; 87-90° C. Elemental Analysiscalculated for C₁₄H₁₅C₁₂NO₃: C, 53.18; H, 4.78; N, 4.43; Found: C,53.34; H, 4.71; N, 4.51.

2.2.3 Synthesis of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Combine Raney nickel (24 lb) and an aqueous concentrated ammoniasolution (19 lb). Add a solution of3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester (15 lb)and ethanol (117 lb) in a pressure reactor. Hydrogenate at 200 psi and35° C. After 20 hours, cool, vent the vessel, purge with nitrogen, andfilter. Rinse the solids with ethanol. Evaporate the filtrate in vacuoto give a residue. Crystallize the residue by dissolving in ethylacetate and triturate the solution with heptane to give a solid. Collectthe solid to give the title compound. Elemental Analysis calculated forC₁₄H₁₅C₁₂NO₃: C 53.18; H 4.78; N 4.43; Found: C, 53.18; H, 4.72; N,4.46.

2.2.4 Synthesis of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Combine 3-cyano-3-(3,4-dichlorophenyl)pentanedioic acid diethyl ester(6.7 kg, wet cake containing isopropanol, about 3% L.O.D.) and 3Cethanol (52 kg) in a pressure reactor. Add Raney nickel in water (17.5kg, about 11 kg of active catalyst) and an aqueous concentrated ammoniasolution (8.7 kg). Hydrogenate at 200 psi and 35° C. When the reactionis complete, cool, vent the reactor, and purge with nitrogen. Filterthrough a filter bag, rinse with ethanol, and then filter through a 0.2micron cartridge filter, and rinse the solids with ethanol. Evaporatethe filtrate in vacuo to give the title compound.

2.2.5 Synthesis of (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Combine Raney nickel (twice washed with water and twice washed withethanol, 3.6 kg), 3-cyano-3-(3,4-dichlorophenyl)pentanedioic aciddiethyl ester (1260 g, 3.51 mol), ethanol (9 L), and an aqueousconcentrated ammonia solution (1.6 L) in a 5 gallon autoclave.Hydrogenate at 55 psi. After 20 hours, vent the vessel, purge withnitrogen, and filter. Rinse the solids with ethanol (about 1 L,).Evaporate the filtrate in vacuo to give a residue. Combine the residueand ethyl acetate (10 L) and extract twice with water (1 L) and thenwith brine. Dry the organic layer over MgSO₄, filter, and concentrate invacuo to give a residue. Crystallize the residue from ethyl acetate(about 1.8 L) and heptane (about 7.2 L) to give a solid. Collect thesolid to give the title compound: mp; 98-99° C.

2.3 Synthesis of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Cool a solution of lithium aluminum hydride (450 mL, 1M in THF, 450mmol) to −10° C. in a ice/acetone bath. Add dropwise, a solution ofsulfuric acid (12 mL, 99.999%, 225.3 mmol) in THF (35 mL). (Use cautionwhen adding the sulfuric acid to the THF and also when adding thesulfuric acid/THF solution to the lithium aluminum hydride solution).After the addition is complete, stir for 1 hour. Warm to ambienttemperature and stir for 2 hours. Add dropwise, a solution of(3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester(23.2 g, 73.4 mmol) in THF (70 mL). Heat to 45-50° C. for 36 hours. Coolin an ice bath. Add dropwise, a solution of THF/water (1/1, 70 mL).Filter and rinse the filter cake with THF and dichloromethane, retainthe filtrate. Combine the filter cake with THF/water/15% sodiumhydroxide solution (1 L/70 mL/20 mL) and vigorously stir for 2 hours.Filter and combine the filtrate with the filtrate obtained above.Concentrate the combined filtrates in vacuo to obtain a residue.Dissolve the residue in dichloromethane and dry over MgSO₄, filter, andconcentrate in vacuo to obtain a residue. Recrystallize the residue fromdiethyl ether to give the title compound: R_(f)=0.27 (silica gel,9:1:0.2; dichloromethane/methanol/ammonium hydroxide); mp; 91-94° C.Elemental Analysis calculated for C₁₂H₁₅Cl₂NO: C,55.40; H, 5.81; N,5.38; Found: C, 55.64; H, 5.88; N, 5.20.

2.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-(3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (288 mg,1.1 mmol) and 4-methylmorpholine (0.25 mL, 2.27 mmol) in dichloromethane(10 mL). Cool to −78° C. in a dry-ice/acetone bath. Add a solution of3,4,5-trimethoxybenzoyl chloride (250 mg, 1.1 mmol) in dichloromethane(3 mL). Warm the reaction mixture to 0° C. After 1 hour, extract thereaction mixture with 1M hydrochloric acid solution and 5% sodiumbicarbonate solution. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting sequentially with 50% ethyl acetate/hexane and 6%methanol/dichloromethane to give the title compound: R_(f)=0.38 (silicagel, 6% methanol/dichloromethane).

2.5.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 1.5 using1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.65 (silica gel, 6%methanol/dichloromethane).

2.5.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(200 mg, 0.44 mmol) and N,N-diisopropylethylamine (0.17 mL, 0.97 mmol)in dichloromethane (25 mL). Cool in a ice-bath. Add dropwise,methanesulfonyl chloride (0.066 g, 0.57 mmol). After 2 hours, extractwith 1 M hydrochloric acid solution and 5% sodium bicarbonate solution.Dry the organic layer over MgSO₄, filter, and concentrate in vacuo togive the title compound: R_(f)=0.42 (silica gel, 6%methanol/dichloromethane); mp; 64.0-66.0° C.

2.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 3

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

3.1.1 Synthesis of 3-cyano-3-phenylpentanedioic acid diethyl ester

Prepare by the method of Example 1.1 using phenylacetonitrile (5.85 g,50.0 mmol). Purify by chromatography on silica gel eluting with 20%ethyl acetate in hexane to obtain the title compound: R_(f)=0.23 (silicagel, 20% ethyl acetate in hexane).

3.1.2 Synthesis of 3-cyano-3-phenylpentanedioic acid diethyl ester

Combine phenylacetonitrile (5.85 g, 50.0 mmol) and tetrahydrofuran (140mL). Cool to about 5° C. Add dropwise, a solution of sodiumbis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol).When the addition is complete, warm the reaction mixture to ambienttemperature and allow to stir for 1 hour. Transfer the above solutionvia cannula into a cooled (−8° C.) solution of ethyl bromoacetate (84.5mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that thetemperature of the reaction mixture does not rise above about 20° C.Allow to stir at ambient temperature. After 18 hours, dilute withdiethyl ether (1.5 L) and extract with saturated aqueous solution ofammonium chloride, then water, and then saturated aqueous solution ofsodium chloride. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to obtain a residue. Distill the residue bybulb-to-bulb distillation to give the title compound: bp; 140-150° C. at0.2 mm Hg.

3.1.3 Synthesis of 3-cyano-3-phenylpentanedioic acid diethyl ester

Combine phenylacetonitrile (175.5 g, 1.5 mol) and tetrahydrofuran (1.95L). Cool to about 0° C. Add dropwise over about 15 minutes, a solutionof sodium bis(trimethylsilyl)amide (3.2 L, 1 M in tetrahydrofuran, 3.2mol). When the addition is complete, warm the reaction mixture toambient temperature and allow to stir for 1 hour. Transfer the abovesolution over about 45 minutes into a cooled (about −20° C.) solution ofethyl bromoacetate (510 g, 3.05 mol) in tetrahydrofuran (1.95 L). Warmto ambient temperature and allow to stir. After 18 hours, dilute withdiethyl ether (3 L) and water (1.5 L). Extract twice with saturatedaqueous solution of ammonium chloride (2.25 L) and then brine. Dry theorganic layer over MgSO₄, filter, and concentrate in vacuo to obtain aresidue. Distill the residue by bulb-to-bulb distillation to give thetitle compound: bp; 180-190° C. at 30 mm of Hg. Elemental Analysiscalculated for C₁₆H₁₉NO₄: C, 66.43; H, 6.62; N, 4.84. Found: C, 66.34;H, 6.57; N, 4.82.

3.2.1 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethylester

Prepared by the method of Example 2.2.2 using3-cyano-3-phenylpentanedioic acid diethyl ester to give the titlecompound: R_(f)=0.60 (silica gel, 6% methanol/dichloromethane).

3.2.2 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethylester

Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (93 g, 321 mmol)and ethanol (400 mL) in a 2 gallon pressure reactor. Add Raney nickel(280 g). Heat to 50° C. and charge with 200 psi of hydrogen. After 15minutes, vent the reactor and add aqueous concentrated ammonia solution(120 mL) Charge the reactor with 200 psi of hydrogen. After 7 hours,vent the reactor and allow to stand for 18 hours. Filter through acelite pad and rinse the solids with ethanol. Evaporate the filtrate invacuo to obtain a residue. Combine the residue and 1/5 diethylether/hexane (500 mL) and cool to −20° C. After 18 hours, decant and add1/5 diethyl ether/hexane (500 mL) and cool to −20° C. to give a solid.Collect the solid by filtration and triturate with 1/5 diethylether/hexane (500 mL). Filter and dissolve in diethyl ether (300 mL) andadd hexane (700 mL) to give a solid. Collect the solid by filtration anddry to give the title compound. Elemental Analysis calculated forC₁₄H₁₇NO₃: C, 68.00; H, 6.93; N, 5.66; Found: C, 67.63; H, 6.99; N,5.81.

3.2.3 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethylester

Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (396.6 g, 1.37mol) and ethanol (4 L), and concentrated aqueous ammonia (530 mL), in atwo gallon autoclave. Add Raney nickel (410 g). Heat to 24° C. andcharge with 205 psi of hydrogen. After 26 hours, vent the reactor andpurge with nitrogen. Filter the reaction mixture through a celite padand rinse the solids with ethanol (1.5 L). Evaporate the filtrate invacuo to give the title compound.

3.2.4 Synthesis of (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethylester

Combine 3-cyano-3-phenylpentanedioic acid diethyl ester (243 g, 0.84mol) and ethanol (2.5 L), concentrated aqueous ammonia (325 mL), andRaney nickel (250 g, prewashed three times with water) in a two gallonautoclave. Charge with 200 psi of hydrogen. Heat to 50° C. After 24hours, vent the reactor and purge with nitrogen. Filter the reactionmixture through a celite pad and rinse the solids with ethanol (1 L).Evaporate the filtrate in vacuo to give the title compound.

3.3.1 Synthesis of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 1.3 using(3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (8.7 g, 35 mmol)to give, after recrystallization from dichloromethane/diethyl ether, thetitle compound: mp; 115.0-117.0° C.; R_(f)=0.03 (silica gel, 6%methanol/dichloromethane). Elemental Analysis calculated for C₁₂H₁₇NO:C, 75.36; H, 8.96; N, 7.32; Found: C, 75.78; H, 8.96; N, 7.45.

3.3.2 Synthesis of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (301 g,1.25 mol) and tetrahydrofuran (3.5 L). Cool to about 5° C. Slowly, addportionwise over about 45 minutes a solution of lithium aluminum hydridein tetrahydrofuran (3.9 L, 1 M, 3.9 mol). After the addition is completeheat to 60° C. After 18 hours, cool in an ice-bath. Addwater/tetrahydrofuran 1/1 (1.95 L) dropwise at such a rate that thetemperature of the reaction mixture does not rise above 20° C. Dilutethe reaction mixture with tetrahydrofuran (2.25 L) and stir. After 1.5hours, filter the reaction mixture. Suspend the solids in diethyl ether(3 L) and filter. Combine the filtrates and concentrate the in vacuo togive a residue. Combine the residue and dichloromethane (4 L) andextract three times with water (1 L). Dry the organic layer over MgSO₄,filter, and concentrate in vacuo to obtain a solid. Triturate the solidwith diethyl ether (0.3 L), collect by filtration, rinse with diethylether, and dry to give the title compound: R_(f)=0.12 (silica geldichloromethane/methanol/concentrated aqueous ammonia, 9/1/0.1).

3.3.3 Synthesis of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (3-phenyl-5-oxopyrrolidin-3-yl)acetic acid ethyl ester (171 g,0.69 mol) and tetrahydrofuran (2 L). Cool to about 5° C. Slowly, addover about 15 minutes a solution of lithium aluminum hydride intetrahydrofuran (2.24 L, 1 M, 2.24 mol). After the addition is completeheat to about 60° C. After 18 hours, cool in an ice-bath. Slowly quenchby adding a saturated aqueous solution of sodium potassium tartrate (208mL). After the quench is complete, add Na₂SO₄ (100 g) and celite (150 g)and stir. After 3 hours, dilute the reaction mixture withtetrahydrofuran (2 L) and filter. Suspend the solids in diethyl ether (2L) and and filter. Combine the filtrates and concentrate the in vacuo togive the title compound: mp; 106-110° C. R_(f)=0.2 (silica geldichloromethane/methanol/concentrated aqueous ammonia, 9/1/0.1).

3.4.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)-pyrrolidine

Prepared by the method of Example 1.4.1 using3-phenyl-3-(2-hydroxyethyl)pyrrolidine to give the title compound:R_(f)=0.38 (silica gel, 6% methanol/dichloromethane).

3.4.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Prepared by the method of Example 1.4.2 using3-phenyl-3-(2-hydroxyethyl)pyrrolidine to give the title compound:R_(f)=0.05 (silica gel, ethyl acetate).

3.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.5g, 1.3 mmol), N,N-diisopropylethylamine (0.5 mL, 2.9 mmol), andanhydrous dichloromethane (17 mL). Cool to 0° C. using an ice bath. Addmethanesulfonyl chloride (201 mg, 1.36 mmol). After 2 hours, dilute thereaction mixture with dichloromethane and extract with a saturatedsolution of sodium bicarbonate. Dry the organic layer over Na₂SO₄,filter, and concentrate in vacuo to give the title compound: R_(f)=0.26(silica gel, ethyl acetate).

3.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(1.0 g, 2.2 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.72 g, 2.2mmol), and N,N-diisopropylethylamine (0.75 mL, 4.4 mmol) in acetonitrile(70 mL). Heat to reflux. After 72 hours, cool and pour the reactionmixture into dichloromethane (700 mL). Extract twice with water and thenbrine. Dry the organic layer over Na₂SO₄, filter, and concentrate invacuo to obtain a residue. Chromatograph the residue on a short columnof silica gel eluting with 25% methanol/0.6% concentrated aqueousammonia/ethyl acetate to give the title compound: R_(f)=0.38 (silicagel; 25% methanol/0.6% concentrated aqueous ammonia/ethyl acetate).

3.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinemethanesulfonic acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4)diazepan-1-yl)ethyl)-3-phenylpyrrolidine (1.45 g) and ethyl acetate (40mL). Add dropwise a solution of methanesulfonic acid (0.42 g, 8.7 mmol)in ethyl acetate (5 mL). After 18 hours, add diethyl ether (100 mL).Decant solvent and add diethyl ether. Again, decant solvent, add diethylether, and evaporate in vacuo to give a solid. Dry the solid in vacuo at56° C. to give the title compound: mp; 68-85° C.

EXAMPLE 4

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethyoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

4.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-oxoethyl)pyrrolidine

Combine oxalyl chloride (0.32 g, 2.5 mmol) with dichloromethane (6 mL)and cool to −60° C. Add dropwise a solution of dimejthyl sulfoxide (0.39g, 5.0 mmol) in dichloromethane (1 mL) while maintaining the temperaturebelow −50° C. After addition is complete, stir for 5 minutes. Add asolution of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(1.03 g, 2.3 mmol) in dichloromethane (2 mL) and stir. After 15 minutes,cool the reaction to 78° C. and add dropwise triethylamine (15.6 mL,11.3 mmol). Allow the reaction to warm to ambient temperature and stirfor 30 minutes. Pour the reaction mixture into water. Extract threetimes with dichloromethane. Combine the organic layers and dry overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with ethyl acetate to give, afterdrying in vacuo at 90° C., the title compound: mp; 45-48° C. R_(f)=0.28(silica gel, ethyl acetate).

4.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-oxoethyl)pyrrolidine(0.51 g, 1.13 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.40 g, 1.36mmol), and silica gel (about 2 g) in methanol (24 mL) and stir. After 3days, add sodium cyanoborohydride (0.71 g, 11.3 mmol) and 3 Å molecularsieves (about 12 g) and stir under an inert atmosphere. After 18 hours,add a solution of 2 M sodium hydroxide and dichloromethane and stir.After 18 hours, filter, separate the layers in the filtrate, and extractthe organic layer with brine. Dry the organic layer over Na₂SO₄, filter,and evaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 1/1 ethyl acetate/methanol to give, after dryingin vacuo at 82° C., the title compound: mp; 55-65° C. R_(f)=0.36 (silicagel, 1/1 ethyl acetate/methanol). Elemental Analysis calculated forC₃₈H₄₇C₁₂N₅O₅: C, 62.98; H, 6.54; N, 9.66; Found: C, 62.65; H, 6.65;N,9.51.

EXAMPLE 5

(R)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

5.1.1 Resolution of(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(R)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrirolidine(R,R)-di-p-anisoyltartaric acid salt

Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g,38.5 mmol) and butanone. Add a solution of (R,R)-di-p-anisoyltartaricacid (1.6 g, 38.0 mmol) in butanone (80 mL). Heat to reflux. After 15minutes, cool to ambient temperature and then cool further in ansalt-ice bath. Filter the solid that forms and rinse with butanone.Recrystallize the solid from water/methanol to give(S)-(−)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt: mp; 201-204° C. (dec). [α]² _(D)⁰=18.9° (c=0.60, dimethylsulfoxide). X-ray diffraction analysis of asingle crystal confirms the (S)-configuration. Analysis on HPLC, on ananalytical sample of the free amine obtained by extraction, using aCHIRALPAK AD 25 cm×0.46 cm column eluting withpentane/methanol/triethylamine (80/10/0.1) with a flow rate of 1.0mL/minute indicates an enantiomeric excess of 96%, (96% ee), retentiontime of the (S)-isomer 11.2 minutes, retention time of the (R)-isomer14.5 minutes.

5.1.2 Resolution of(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(R)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine hydrochloricacid salt

Combine (R,R)-di-p-anisoyltartaric acid (0.8 g, 19 mmol) and aqueous 12M hydrochloric acid solution (0.16 mL, 19 mmol) in water/methanol (10mL)/(10 mL). Heat to reflux. Add dropwise, a solution of3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 38.5 mmol)in methanol (10 mL). After 15 minutes, slowly cool to ambienttemperature. Filter the solid that forms and rinse with water to give(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid: mp; 201-204° C. (dec). Analysis byHPLC, as described in Example 5.1.1 indicates an enantiomeric excess of97%, (97% ee).

5.1.3 Synthesis and resolution of(S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt

Combine (3-(3,4-dichlorophenyl)-5-oxopyrrolidin-3-yl)-acetic acid ethylester (40 lb) and tetrahydrofuran (260 lb). Purge the vessel withnitrogen. Add a solution of borane dimethylsulfide complex (38 lb, 2 Msolution in tetrahydrofuran). Heat to reflux. After 60 hours, distilluntil the internal temperature rises to about 70° C. and then slowlyquench the reaction with methanol (650 lb). Add water (650 lb). Addmethanesulfonic acid (16 lb). Heat to reflux and remove the distillateto remove most of the residual tetrahydrofuran. Combine methanol (about18 gal) and (R,R)-di-p-anisoyltartaric acid (32 lb). Heat to reflux andtransfer to the vessel containing the above residue. Add seed crystalsand slowly cool to 10° C. to give a solid. Collect the solid and combinemethanol (145 gal) and water (145 gal). Heat to reflux. After 1 hour,slowly cool to 10° C. to give a solid. Collect the solid to give, afterdrying, the title compound.

5.1.4 Resolution to give(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(4.5 g, 9.9 mmol) and dichloromethane/pyridine (70 mL, 6/1). Add aceticanhydride (1.04 mL, 11.0 mmol) and 4-dimethylaminopyridine (50 mg, 0.41mmol). After 2 hours, concentrate the reaction mixture in vacuo toobtain a residue. Dissolve the residue in ethyl acetate and extract with1M hydrochloric acid solution (2×200 mL), saturated sodium bicarbonatesolution, and saturated sodium chloride solution. Dry the organic layerover MgSO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with ethyl acetate togive1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine:R_(f)=0.38 (silica gel, ethyl acetate). Elemental Analysis calculatedfor C₂₄H₂₇Cl₂NO₆: C 58.07; H 5.48; N 2.82; Found: C, 57.67; H, 5.46; N,2.84.

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine(6.6 g, 13.3 mmol) and dichloromethane (100 mL). Add silica gel (32 g).Concentrate the slurry in vacuo to give a residue. Suspend the residuein phosphate buffer (800 mL, 0.1 M, pH=7.5, the buffer was prepared with11.5 g H₃PO₄ (85%) diluted to 1 L with deionized water and thenadjusting the pH with solid potassium hydroxide pellets to 7.5) toobtain a slurry. Treat the slurry with Lipase (13 g, EC_(3.1.1.3), TypeVII, from Candida cylindracea). Monitor the reaction by HPLC on aCHIRALPAK AD 25 cm×0.46 cm column eluting with pentane/ethanol/methanol(80/15/5) with a flow rate of 1.0 mL/minute. Prepare an aliquot foranalysis as follows: centrifuge the solution for 10 minutes at 14000cm⁻¹, remove the supernatant and concentrate under a nitrogen stream toobtain a residue, dissolve the residue in dichloromethane (ca. 1 mL) andinject on the column for analysis. When the enantiomeric excess (ee) issatisfactory (>95% ee) for the (+)-acetate, filter the reaction. Rinsethe solids with dichloromethane (8×500 mL). Extract the filtrate withdichloromethane (8×500 mL). Chromatograph the solids on silica geleluting with 6% methanol/dichloromethane. Concentrate the combinedeluant and extracts in vacuo to obtain a residue. Dissolve the residuein dichloromethane, dry over MgSO₄, filter, and concentrate in vacuo togive a residue. Chromatograph the residue on silica gel eluting withethyl acetate to give(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine:R_(f)=0.38 (silica gel, ethyl acetate). Elemental Analysis calculatedfor C₂₄H₂₇Cl₂NO₆•0.5 H₂O: C, 57.14; H, 5.59; N, 2.78; Found: C, 57.37;H, 5.45; N, 2.87. [ ]² _(D) ⁰=+36.4° (c=0.894, chloroform).

Combine(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine(670 mg, 1.35 mmol) and aqueous lithium hydroxide solution (4.2 mL, 1M)in methanol (15 mL). After 3.5 hours, concentrate in vacuo to give aresidue. Dissolve the residue in dichloromethane and extract with 1Mhydrochloric acid solution and saturated sodium bicarbonate solution.Dry the organic layer over MgSO₄, filter, and concentrate in vacuo toobtain a residue. The residue was dried under high vacuum for 18 hoursto give(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine:R_(f)=0.11 (silica gel, ethyl acetate).

5.2.1 Synthesis of(S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (0.14 g, 0.21 mmol) ethyl acetate(15 mL), acetonitrile (6 mL), water (6 mL), and sodium bicarbonate (0.09g, 1.03 mmol). Cool to 0° C. in an salt-ice bath. Add3,4,5-trimethoxybenzoyl chloride (0.048 g, 0.21 mmol). After 30 minutes,warm to ambient temperature. After 30 minutes at ambient temperature,partition the reaction mixture between ethyl acetate and brine. Extractthe organic layer with 1 M hydrochloric acid solution, then saturatedaqueous sodium bicarbonate solution. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give the title compound: R_(f)=0.11(silica gel, ethyl acetate). [a]² _(D) ⁰=+61.7°(c=1.01, methanol).

5.2.2 Synthesis of(S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (6.0 g, 8.84 mmol) acetone (40 mL),water (40 mL), sodium hydroxide (0.335 g, 8.87 mmol), and sodiumbicarbonate (3.73 g, 8.87 mmol). Cool to about 0° C. Add a solution of3,4,5-trimethoxybenzoyl chloride (2,2 g, 9.7 mmol) in acetone (12 mL)over about 15 minutes. After 3 hours, partition the reaction mixturebetween ethyl acetate and brine. Extract the organic layer with 1 Msodium hydroxide solution, saturated sodium bicarbonate solution, 1 Mhydrochloric acid solution, then brine. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give the title compound:R_(f)=0.11 (silica gel, ethyl acetate).

5.3 Synthesis of(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using(S)-(+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(1.351 mmol) and methanesulfonyl chloride (0.14 ml,, 1.81 mmol) to givethe title compound: R_(f)=0.27 (silica gel, ethyl acetate).

5.4.1 Synthesis of(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Prepare by the method of Example 1.6 using(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

5.4.2 Synthesis of(R)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Combine 3,4,5-trimethoxybenzoic acid (3.5 kg, 16.5 mol) and1,2-dimethoxyethane (14.2 kg) and dimethyl formamide (4 g). Cool in anice bath. Add oxalyl chloride (2.99 kg, 23.5 mmol) over about 50 minutesnot allowing the temperature of the reaction to raise above about 19° C.After 20 hours, concentrate in vacuo at 25° C. to remove about 3.7 kg ofdistillate to give a solution of 3,4,5-trimethoxybenzoyl chloride.

Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (9.05 kg, 13.3 mol), potassiumcarbonate (6.42 kg) in acetone (27.2 kg). Cool to about 5° C. and addwater (8.3 gal). Cool to about 3° C. and slowly add a solution of3,4,5-trimethoxybenzoyl chloride (14.0 kg, 26.9% in 1,2-dimethoxethane,16.3 mol) over about 25 minutes. When the reaction is complete, warm to25° C. Dilute the reaction mixture with toluene (36.35 kg). Separate thelayers and extract the organic layer with a solution of water (2 gal)and 3 M aqueous hydrochloric acid solution (2 kg) and then brine.Concentrate the organic layer in vacuo until about 5 gallons remains.Add toluene (18.2 kg) and again concentrate in vacuo until about 5gallons remain. Add toluene (36.15 kg) and cool to about −3° C. AddN-methylmorpholine (6.85 kg, 67.7 mol) and then methanesulfonyl chloride(3.40 kg, 29.7 mol). When the reaction is complete, add water (4.8 gal)and warm to about 25° C. Separate the layers and extract the organiclayer with a 3 M aqueous hydrochloric acid solution (18.1 kg). Separatethe layers to give a solution of(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine.

Combine the above solution of(S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine,potassium carbonate (4.07 kg, 29.5 mol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (12.0 mol), andwater (3.3 gal). Heat to about 70° C. When the reaction is complete,dilute the reaction mixture with methyl ethyl ketone (18.1 kg) and after15 minutes of stirring, separate the layers. Extract the organic layerwith water (3.4 gal) and then concentrate in vacuo to give the titlecompound.

EXAMPLE 6

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxethyl)-1H-benzimidazol-2-yl)diazepan-1-yl)ethyl-3-(3,4-dimethylphenyl)pyrrolidine

6.1.1 Synthesis of 3-cyano-3-(3,4-dimethylphenyl)pentanedioic aciddiethyl ester

Combine 3,4-dimethylphenylacetonitrile (50.0 mmol) and tetrahydrofuran(140 mL). Cool to about 5° C. Add dropwise a solution of sodiumbis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol).When the addition is complete, warm the reaction mixture to ambienttemperature and allow to stir for 1 hour. Transfer the above solutionvia cannula into a cooled (−8° C.) solution of ethyl bromoacetate (84.5mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that thetemperature of the reaction mixture does not rise above 20° C. Allow tostir at ambient temperature. After 18 hours, dilute with diethyl ether(1.5 L) and extract with saturated aqueous solution of ammoniumchloride, then water, and then saturated aqueous solution of sodiumchloride. Dry the organic layer over MgSO₄, filter, and concentrate invacuo to give the title compound.

6.1.2 Synthesis of 3-cyano-3-(3,4-dimethylphenyl)pentanedioic aciddiethyl ester

Cool a solution of sodium bis(trimethylsilyl)amide (723 mL, 1 M intetrahydrofuran, 723 mmol) to 0° C. in an ice bath. Add a solution of3,4-dimethylphenylacetonitrile (50.0 mmol) in tetrahydrofuran (130 mL)over about 1.5 hours. When the addition is complete, warm the reactionmixture to ambient. temperature and allow to stir. After 2 hours,transfer the above solution via cannula into a cooled (−50° C.) solutionof ethyl bromoacetate (126 g, 757 mmol) in tetrahydrofuran (250 mL).After the transfer is complete, allow the reaction mixture to warm toambient temperature. After 18 hours, dilute with diethyl ether (500 mL)and extract with water, 1 M hydrochloric acid solution, saturatedaqueous solution of sodium bicarbonate, and then brine. Dry the organiclayer over MgSO₄, filter, and concentrate in vacuo to give a residue.Recrystallize the residue from diethyl ether to give the title compoundas a solid.

6.2.1 Synthesis of (3-(3,4-dimethylphenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Prepare by the method of Example 2.2.2 using3-cyano-3-(3,4-dimethylphenyl)pentanedioic acid diethyl ester to givethe title compound.

6.2.2 Synthesis of (3-(3,4-dimethylphenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Combine 3-cyano-3-(3,4-dimethylphenyl)pentanedioic acid diethyl ester(56 g, 177 mmol) and ethanol (500 mL) in a Parr bottle. Add Raney nickel(50 g) and an aqueous concentrated ammonia solution (85 mL). Hydrogenateat 50° C. and 100 psi for 48 h. Filter through a celite pad and rinsethe solids with ethanol. Evaporate the filtrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 6%methanol/dichloromethane to give the title compound.

6.3 Synthesis of 3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 2.3 using(3-(3,4-dimethylphenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester togive, after recrystallization from dichloromethane/diethyl ether, thetitle compound: R_(f)=0.35 (silica gel, 85/10/5dichloromethane/methanol/acetic acid).

6.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-(3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrrolidine (20 mmol)and sodium bicarbonate (8.4 g) in acetone (50 mL)/water (50 mL). Add asolution of 3,4,5-trimethoxybenzoyl chloride (4.6 g, 19.9 mmol) inacetone (50 mL). After 3 hours, extract the reaction mixture three timeswith ethyl acetate. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to give the title compound: R_(f)=0.25 (silica gel,6% methanol/dichloromethane).

6.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethylphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethylphenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.44 (silica gel, ethyl acetate).

6.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dimethylphenyl)pyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dimethylphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 7

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine

7.1 Synthesis of 3-cyano-3-(3-chlorophenyl)pentanedioic acid diethylester

Prepare by the method of Example 6.1.1 using 3-chlorophenylacetonitrileto give the title compound. Elemental Analysis calculated forC₁₆H₁₈ClNO₄: C, 59.35; H 5.55: N 4.33: Found: C_(59.47:) H 5.54; N 4.51.

7.2 Synthesis of (3-(3-chlorophenyl)-5-oxolpyrrolidin-3-yl)-acetic acidethyl ester

Prepare by the method of Example 2.2.2 using3-cyano-3-(3-chlorophenyl)pentanedioic acid diethyl ester to give thetitle compound.

7.3 Synthesis of 3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 1.3 using(3-(3-chlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester to givethe title compound: R_(f)=0.30 (silica gel, 85/10/5dichloromethane/methanol/acetic acid).

7.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-(3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (4.5 g, 20mmol) and sodium bicarbonate (8.4 g) in acetone (50 mL)/water (50 mL).Add a solution of 3,4,5-trimethoxybenzoyl chloride (4.6 g, 19.9 mmol) inacetone (50 mL). After 3 hours, extract the reaction mixture three timeswith ethyl acetate. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to give the title conmpound: R_(f)=0.46 (silicagel, 6% methanol/dichloromethane).

7.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3-chlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(3-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.47 (silica gel, ethyl acetate).

7.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3-chlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.82 g, 1.65 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.04 g, 1.91 mmol), and N,N-diisopropylethylamine (1.3 mL, 7.43mmol) in acetonitrile (50 mL). Heat to reflux. After 2 days, cool anddilute the reaction mixture with ethyl acetate (300 mL). Extract with asaturated aqueous sodium bicarbonate solution and then brine. Dry overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with 24% methanol/ethyl acetatecontaining concentrated aqueous ammonia (20 mL/3L) to give the titlecompound.

7.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidinefumaric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3-chlorophenyl)pyrrolidine(0.76 g) and fumaric acid (0.31 g, 2.68 mmol) in methanol (30 mL). Addethyl acetate (100 mL) and stir. After 3 days, evaporate in vacuo togive a residue. Combine the residue with diethyl ether (200 mL) andstir. After 18 hours, decant and add diethyl ether and stir. After 6days, decant, collect the solid which forms, and dry in vacuo to givethe title compound: mp; 66-78° C.

PREPARATION 3

4-(1H-Benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt

Combine [1,4]diazepane (33.9 g, 340 mmol) and water (250 mL). Add methylorange and adjust the pH using 3 M aqueous hydrochloric acid solutionuntil the indicator turns red. Add dropwise, ethyl chloroformate (38 mL,400 mmol) over about 2.5 hours while maintaining the pH using firstaqueous sodium acetate and then aqueous sodium hydroxide solution. Afterthe addition is complete adjust the pH to 8 using aqueous sodiumhydroxide solution and extract three times with diethyl ether. Discardthe organic extracts and saturate the aqueous layer with potassiumcarbonate. Extract three times with diethyl ether. Combined organiclayers from the second extraction, dry the over Na₂SO₄, filter, andevaporate in vacuo to give a 1-ethoxycarbonyl[1,4]diazepane.

Combine 1-ethoxycarbonyl[1,4]diazepane (36.6 g, 212 mmol) and2-chlorobenzimidazole (18.0 g, 106 mmol). Heat to 130° C. After 4 hours,cool to ambient temperature and add hot methanol to dissolve thereaction mixture. Partition the methanol solution betweendichloromethane (700 mL) and a solution of sodium hydroxide (20 g) inwater (500 mL). Separate the layers and extract the aqueous layer threetimes with dichloromethane. Combine the organic layers, extract withbrine, dry over Na₂SO₄, filter, and evaporate in vacuo to give a solid.Triturate the solid with ethyl acetate (100 mL) and cool to 0° C.Collect solid by filtration and dry in vacuo to give1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane.

Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (16.7 g,58 mmol) and aqueous 48% hydrobromic acid solution (80 mL). Heat toreflux. After 3 hours, cool to ambient temperature, add to ethanol (700mL), and cool to 0° C. to give a solid. Combine the solid with aqueous48% hydriodic acid (80 mL) and water (150 mL). Heat on a steam bath.After about 1 hour, cool to ambient temperature, dilute with ethanol(500 mL), and add to diethyl ether (8 L) to give a solid. Collect solidby filtration and dry in vacuo to give the title compound: mp; >290° C.

EXAMPLE 8

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

8.1.1 Resolution of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine hydrochloride salt

Combine (R,R)-di-p-anisoyltartaric acid (1.10 g, 2.62 mmol) inwater/methanol (13.6 mL/13.6 mL). Add 12 M hydrochloric acid solution(0.217 mL, 2.63 mmol). Add a hot solution of3-phenyl-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 5.23 mmol) in methanol(13.6 mL). Heat to reflux. After 30 minutes, slowly cool to ambienttemperature to give a solid. Collect the solid by filtration andrecrystallize the solid twice from methanol/water, once frommethanol/2-butanone, and once from ethanol to give(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid. After conversion of a sample to the 3,4,5-trimethoxybenzamideusing sodium carbonate and 3,4,5-trimethoxybenzoyl chloride inacetone/water, analysis on HPLC using a CHIRALPAK AD (10 μm×4.6 cm×250cm) column eluting with pentane/ethanol/methanol/triethylamine(80/15/5/0.1) with a flow rate of 1.5 mL/minute indicates anenantiomeric excess of 98%, (98% ee), retention time 22.30 minutes forthe 3,4,5-trimethoxybenzamide of the isomer prepared from the (−)-isomerof (R,R)-di-p-anisoyltartaric acid salt.

8.1.2 Resolution of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt

Add a hot solution of 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (5.0 g,20.2 mmol) in ethanol (100 mL) to a refluxing solution of(R,R)-di-p-anisoyltartaric acid (8.46 g, 20.2 mmol, containing a smallamount of acetone) in ethanol (200 mL). After the addition is complete,slowly cool to ambient temperature to give a solid. Collect the solid byfiltration and recrystallize the solid three times from ethanol to give(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt: mp; 178.0-179.0° C. Elemental Analysis calculated forC₁₂H₁₇NO•C₂₀H₁₈O₁₀: C, 63.05; H 5.79; N 2.30; Found: C 62.72; H 5.80; N2.33. After conversion of a sample to the 3,4,5-trimethoxybenzamideusing sodium carbonate and 3,4,5-trimethoxybenzoyl chloride inacetone/water, analysis on HPLC using a CHIRALPAK AD (10 μm×4.6 cm×250cm) column eluting with pentane/ethanol/methanol/triethylamine(80/15/5/0.1) with a flow rate of 1.5 mL/minute indicates anenantiomeric excess of 99.9%, (99.9% ee), retention time 22.30 minutesfor the 3,4,5-trimethoxybenzamide prepared from the (−)-isomer of(R,R)-di-p-anisoyltartaric acid salt.

Upon standing, the mother liquors from above give a solid. Collect thesolid by filtration and recrystallize twice from ethanol to give(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt: mp; 175.0-176.0° C. Elemental Analysis calculated forC₁₂H₁₇NO•C₂₀H₁₈O₁₀•0.8 C₃H₆O: C, 62.98; H, 6.11; N, 2.13; Found: C,62.86; H, 5.94; N, 2.33. After conversion of a sample to the3,4,5-trimethoxybenzamide using sodium carbonate and3,4,5-trimethoxybenzoyl chloride in acetone/water, analysis on HPLCusing a CHIRALPAK AD (10 μm×4.6 cm×250 cm) column eluting withpentane/ethanol/methanol/triethylamine (80/15/5/0.1) with a flow rate of1.5 mL/minute indicates an enantiomeric excess of 99.9%, (99.9% ee),retention time 10.26 minutes for the 3,4,5-trimethoxybenzamide preparedfrom the (+)-isomer of (R,R)-di-p-anisoyltartaric acid salt.

8.1.3 Resolution of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (99.2 g, 659 mmol) andethanol (2.5 L). Heat to reflux. Add a refluxing solution of(R,R)-di-p-anisoyltartaric acid (212 g, 507 mmol) in ethanol (5.07 L).After the addition is complete, slowly cool to ambient temperature withstirring to give an oil. Dissolve the oil in ethanol at reflux (595 mL)and add a refluxing solution of (R,R)-di-p-anisoyltartaric acid (49.2 g)in ethanol (1.1 L). Cool to ambient temperature with stirring to give asolid. Collect the solid by filtration and recrystallize from ethanol(3.2 L) to give a second solid. Collect the second solid by filtrationand recrystallize from ethanol (2.6 L), seed with(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt to give (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (121 g).

8.1.4 Resolution of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (101 g, 530 mmol) andethanol (1.92 L). Heat to reflux. Add a refluxing solution of(R,R)-di-p-anisoyltartaric acid (107 g, 410 mmol) in ethanol (3.9 L).Continue to reflux. After 10 minutes, slowly cool to ambient temperatureand add seed crystals. After 18 hours, collect the solid that forms byfiltration, rinse with ethanol (200 mL). Recrystallize twice fromethanol to give (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt: mp; 179-180° C. [α]² _(D) ⁰=−108.8(c=1.02, methanol).

8.1.5 Resolution of (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt

Evaporate the filtrate obtained from collecting the first formed solidin Example 8.14 to give a residue. Dissolve the residue in the minimumamount of hot ethanol (about 450 mL). Reduce the volume to about 300 mLby heating under a stream of nitrogen gas to obtain a solid.Recrystallize the three times from ethanol to give(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt.

8.2.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (3.95 g, 6.48 mmol) and acetone (20mL), water (6 mL), and potassium carbonate (2.70 g, 19.5 mmol). Cool to0° C. in an ice bath. After 30 minutes, add dropwise a solution of3,4,5-trimethoxybenzoyl chloride (1.71 g, 7.4 mmol) in acetone (20 mL).Warm to ambient temperature. After 18 hours, partition the reactionmixture between ethyl acetate and saturated aqueous sodium bicarbonatesolution. Separate the organic layer and extract with brine. Dry theorganic layer over Na₂SO₄, filter, and evaporate in vacuo to give thetitle compound: R_(f)=0.23 (silica gel, ethyl acetate). Analysis on HPLCusing a CHIRALPAK AD (10 μm×4.6 cm×250 cm) column eluting withpentane/ethanol/methanol/triethylamine (80/15/5/0.1) with a flow rate of1.5 mL/minute indicates an enantiomeric excess of 98%, (98% ee),retention time of 22.30 minutes.

8.2.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (56.0 g, 92.1 mmol), sodiumcarbonate (19.5 g, 184 mmol) in ethyl acetate (2 L) and water (2 L).Cool to about 0° C. in an ice bath. After 30 minutes, slowly adddropwise portionwise 3,4,5-trimethoxybenzoyl chloride (21.2 g, 92.1mmol). After the addition is complete, warm to ambient temperature.After 1 hour, dilute the reaction mixture ethyl acetate and extract withwater, 1 M aqueous hydrochloric acid solution, and then brine. Dry theorganic layer over Na₂SO₄, filter, and evaporate in vacuo to give thetitle compound.

8.3 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (2.21 g, 5.51 mmol) andmethanesulfonyl chloride (0.7 mL, 9.0 mmol) to give the title compound:R_(f)=0.47 (silica gel, ethyl acetate).

8.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(5.0 g, 10.7 mmol), 4-(1H-benzimidazol-2-yl)[1,4]diazepane hydriodicacid salt (5.76 g, 12.2 mmol), and N,N-diisopropylethylamine (16 mmol)in acetonitrile (100 mL). Heat to reflux. After 20 hours, cool toambient temperature, dilute with ethyl acetate, and extract with acombination of water (500 mL) and saturated aqueous sodium bicarbonate(100 mL). Extract the organic layer with brine, dry over Na₂SO₄, filter,and evaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 25% methanol/ethyl acetate containing aqueousconcentrated ammonia (20 mL/3L) to give, after drying in vacuo at 56°C., the title compound: mp; 99-107° C. R_(f)=0.27 (silica gel, 30%methanol/ethyl acetate).

EXAMPLE 9

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

9.1.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(5.5 g, 11.9 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl) [1,4]diazepane hydriodic acidsalt (7.0 g, 12.9 mmol), and N,N-diisopropylethylamine (9.0 mL, 51.4mmol) in acetonitrile (100 mL). Heat to reflux. After 18 hours, cool toambient temperature and dilute the reaction mixture with ethyl acetate(400 mL). Extract with a saturated aqueous sodium bicarbonate solutionand then with brine. Dry the organic layer over Na₂SO₄, filter,, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 25% methanol/dichloromethane containing aqueousconcentrated ammonia (20 mL/3 L). Combine the product containingfractions to give a residue. Dissolve the residue in dichloromethane andfilter. Evaporate the filtrate in vacuo to give the title compound: mp;43-48° C.

9.1.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(1.83 g, 3.94 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (2.04 g, 3.75 mmol), potassium iodide ((0.62 g, 3.75 mmol), andtriethylamine (1.15 mL, 8.25 mmol) in acetonitrile (54 mL). Heat toreflux. After 43 hours, evaporate in vacuo, dilute the evaporatedreaction mixture with dichloromethane, extract with a saturated aqueoussodium bicarbonate solution, water, and then with brine. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially withdichloromaethane, then 10% methanol/dichloromethane to give the titlecompound.

9.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinefumaric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.47 g) and fumaric acid (0.17 g) in methanol (about 20 mL). Add ethylacetate (100 mL) and stir. After 18 hours, evaporate in vacuo to give aresidue. Triturate the residue with diethyl ether to give the titlecompound: mp; 82-94° C.

9.3 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinemaleic acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.47 g) and maleic acid (0.17 g) in methanol (15 mL). Add ethyl acetate(100 mL) and stir. After 18 hours, evaporate in vacuo to give a residue.Triturate the residue with diethyl ether to give the title compound: mp;69-79° C.

9.4 Synthesis of1-(3,4,5-trimethoxybenzoyl-(2)3-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.61 g) and methanol (20 mL). Add a solution of hydrochloric acid inmethanol (0.035 mL, 4 M, 1.4 mmol) and stir. After 10 minutes, evaporateinvacuo to give a residue. Dissolve the residue in methanol (about 5 mL)and dilute with diethyl ether (200 mL) to give a solid. Stir for 3hours, allow he solid to settle and decant the solvent. Add diethylether and collect the solid by filtration to give, after drying, thetitle compound: mp; 137-142° C. (shrinks), 145-149° C.

EXAMPLE 10

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

10.1.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 8.2.1 using(+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt to give the title compound: R_(f)=0.23 (silica gel, ethylacetate).

10.1.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (2.0 g, 3.28 mmol) and sodiumbicarbonate (1.11 g, 13.2 mmol) in ethyl acetate (45 mL) and water (45mL). Add 3,4,5-trimethoxybenzoyl chloride (0.76 g, 3.28 mmol). After 2hours, partition the reaction mixture between ethyl acetate (150 mL) andwater (100 mL). Separate the layers and extract the aqueous layer twicewith ethyl acetate. Extract the combined organic layers with a saturatedaqueous sodium bicarbonate solution. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting sequentially with dichloromethane and then5% methanol/dichloromethane to give the title compound.

10.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(prepared from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyLtartaric acid salt) to give the title compound:R_(f)=0.47 (silica gel, ethyl acetate).

10.3.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 9.1 using1-(3,4,5-trimethoxybenzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt to give the title compound.

10.3.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (1.43 g, 3.1 mmol), triethylamine(2.05 mL, 14.75 mmol), sodium iodide (0.46 g, 3.1 mmol), and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.6 g, 2.95 mmol) in acetonitrile (40 ml). Heat to reflux. After40 hours, evaporate in vacuo to give a residue. Partition the residuebetween dichloromethane and water. Separate the layers and extract theorganic layer with a saturated aqueous sodium bicarbonate solution,water, and then brine. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting sequentially with dichloromethane, 5%methanol/dichloromethane, and then 10% methanol/dichloromethane to givethe title compound.

10.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 9.1 using1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (+)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.66 g, 2.3 mmol) and methanol (35mL). Add a solution of hydrochloric acid in dioxane (1.15 mL, 4 M, 4.6mmol). After 1.5 hours, evaporate in vacuo to give a residue. Repeatedlyadd dichloromethane and evaporate in vacuo to give a residue. Trituratethe residue with diethyl ether to give a solid . Collect the solid byfiltration and dry to give the title compound: mp; 147-167° C.

EXAMPLE 11

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazean-1-yethyl-3-(4-chlorophenyl)pyrrolidine

11.1.1 Synthesis of 3-cyano-3-(4-chlorophenyl)pentanedioic acid diethylester

Combine 4-chlorophenylacetonitrile (50.0 mmol) and tetrahydrofuran (140mL). Cool to about 5° C. Add dropwise a solution of sodiumbis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol).When the addition is complete, warm the reaction mixture to ambienttemperature and allow to stir for 1 hour. Transfer the above solutionvia cannula into a cooled (−8° C.) solution of ethyl bromoacetate (84.5mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that thetemperature of the reaction mixture does not rise above about 20° C.Allow to stir at ambient temperature. After 18 hours, dilute withdiethyl ether (1.5 L) and extract with saturated aqueous solution ofammonium chloride, then water, and then saturated aqueous solution ofsodium chloride. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to give the title compound. Elemental Analysiscalculated for C₁₆H₁₈ClNO₄: C, 59.35; H, 5.60; N, 4.33; Found: C, 59.27;H, 5.54; N, 4.33.

11.1.2 Synthesis of 3-cyano-3-(4-chlorophenyl)pentanedioic acid diethylester

Prepare by the method of Example 6.1.2 using 4-chlorophenylacetonitrile(60.65 g, 400 mmol) to give the title compound.

11.2.1 Synthesis of (3-(4-chlorophenyl)-5-oxopyrrolidin-3-yl)acetic acidethyl ester

Prepare by the method of Example 2.2.2 using3-cyano-3-(4-chlorophenyl)pentanedioic acid diethyl ester to give thetitle compound.

11.2.2 Synthesis of (3-(4-chlorophenyl)-5-oxopyrrolidin-3-yl)acetic acidethyl ester

Prepare by the method of Example 6.2.2 using3-cyano-3-(4-chlorophenyl)pentanedioic acid diethyl ester to give thetitle compound.

11.3 Synthesis of 3-(4-chlorophenyl)-3-(2-hydroxyethyl)-pyrrolidine

Prepare by the method of Example 2.3 using(3-(4-chlorophenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester to givethe title compound: R_(f)=0.30 (silica gel, 85/10/5dichloromethane/methanol/acetic acid).

11.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-(3-(4-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(4-chlorophenyl)-3-(2-hydroxyethyl) pyrrolidine (20 mmol) andsodium bicarbonate (8.4 g) in acetone (50 mL)/water (50 mL). Add asolution of 3,4,5-trimethoxybenzoyl chloride (4.6 g, 19.9 mmol) inacetone (50 mL). After 3 hours, extract the reaction mixture three timeswith ethyl acetate. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to give the title compound: R_(f)=0.42 (silica gel,6% methanol/dichloromethane).

11.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(4-chlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(4-chlorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.44 (silica gel, ethyl acetate).

11.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(4-chlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(1.0 g, 2.0 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.2 g, 2.2 mmol), and N,N-diisopropylethylamine (1.4 mL, 8.1 mmol)in acetonitrile (60 mL). Heat to reflux. After 20 hours, cool and dilutethe reaction mixture with ethyl acetate. Extract three times with asaturated aqueous sodium bicarbonate solution, and then brine. Dry theorganic layer over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 25%methanol/ethyl acetate containing concentrated aqueous ammonia 20 mL/3 Lto give the title compound: R_(f)=0.49 (silica gel, 30% methanol/ethylacetate).

11.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidinefumaric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-chlorophenyl)pyrrolidine(0.79 g) and fumaric acid (0.31 g, 2.7 mmol) in methanol (145 mL). Addethyl acetate (150 mL) and stir. After 18 hours, evaporate in vacuo togive a residue. Triturate the residue with diethyl ether to give asolid. Decant the solvent and collect the solid after evaporation invacuo to give the title compound; mp; 74-81° C.

EXAMPLE 12

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)piperidine

12.1 Synthesis of2-(3,4-dichlorophenyl)-4-(t-butyldimethylsilyloxy)butyronitrile

Combine 3,4-,dichlorophenylacetonitrile (10 g, 53.8 mmol) and anhydroustetrahydrofuran (50 mL). Cool in a dry-ice/acetone bath. Add dropwise asolution of lithium bis(trimethylsilyl)amide (64.5 mL, 1 M in THF, 64.5mmol). Add dropwise, 2-(t-butyldimethylsilyloxy)-1-bromoethane (15.43 g,64.5 mmol). When the addition of2-(t-butyldimethylsilyloxy)-1-bromoethane is complete, warm the reactionmixture to ambient temperature. After 12 hours, partition the reactionmixture between ethyl acetate and water. Extract the aqueous layer twicewith ethyl acetate. Combine the organic layers and extract with 1 Mhydrochloric acid solution, dry over Na₂SO₄, filter, and concentrate invacuo to obtain a residue. Chromatograph the residue on silica geleluting with 10% ethyl acetate/hexane to give the title compound:R_(f)=0.42 (silica gel, 10% ethyl acetate/hexane).

12.2 Synthesis of ethyl4-cyano-4-(3,4-dichlorophenyl)-6-(t-butyldimethylsilyloxy)hexanoate

Combine 2-(3,4-dichlorophenyl)-4-(t-butyldimethylsilyloxy)butyronitrile(13.35 g, 38.8 mmol) and anhydrous tetrahydrofuran (50 mL). Cool in adry-ice/acetone bath. Add dropwise a solution of lithiumbis(trimethylsilyl)amide (42.6 mL, 1 M in THF, 42.6 mmol). Add dropwise,ethyl 3-bromopropionate (7.71 g, 42.6 mmol). Warm the reaction mixtureto ambient temperature. After 18 hours, add water. Separate the aqueouslayer and extract three times with ethyl acetate. Combine the organiclayers, dry over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 90% ethylacetate/hexane to give the title compound: R_(f)=0.35 (silica gel, 10%ethyl acetate/hexane).

12.3 Synthesis of3-(3,4-dichlorophenyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-6-oxopiperidine

Combine ethyl4-cyano-4-(3,4-dichlorophenyl)-6-(t-butyldimethylsilyloxy)hexanoate(9.58 g, 21.55 mmol) and cobalt(II)chloride hexahydrate (10.25 g, 43.1mmol) in methanol (200 mL). Cool in an ice-bath, add portionwise sodiumborohydride (8.15 g, 215.5 mmol). After 18 hours, concentrate thereaction mixture in vacuo to obtain a residue. Dissolve the residue indichloromethane and extract with 1M hydrochloric acid solution. Dry theorganic layer over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane to give the title compound: R_(f)=0.46 (silica gel, 1/1ethyl acetate/hexane).

12.4 Synthesis of 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine

Combine a solution of lithium aluminum hydride (42 mL, 1 M in THF, 42.0mmol). Cool to about −10° C. using an isopropyl alcohol/ice bath. Slowlyadd a solution of sulfuric acid (1.15 mL, 21.6 mmol) in tetrahydrofuran(4 mL) at such a rate that the reaction temperature does not rise above−10° C. Stir vigorously and warm to ambient temperature. After 2 hours,add a solution of3-(3,4-dichlorophenyl)-3-(2-(t-butyldimethylsilyloxy)-ethyl)-6-oxopiperidine(5.56 g, 13.85 mmol) in tetrahydrofuran (12 mL). Heat to reflux. After18 hours, add 1/1 tetrahydrofuran/water. After 1 hour, filter and rinsewith dichloromethane. Suspend the solids removed by filtration intetrahydrofuran (400 mL). To the tetrahydrofuran suspension add water(20 mL) and 15% aqueous sodium hydroxide solution (8 mL) and stirvigorously. After 2 hours, filter. Combine the filtrates and concentratein vacuo to give an aqueous suspension. Extract twice withdichloromethane. Dry the organic layers over Na₂SO₄, filter, andconcentrate in vacuo to give the title compound.

12.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine

Combine 3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine (1.08 g,3.94 mmol) and sodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethylacetate/water (50 mL). Cool the reaction mixture to 0° C. with an icebath. Add 3,4,5-trimethoxybenzoyl chloride (0.83 g, 3.58 mmol). Warm toambient temperature. After 18 hours, separate the layers and extract theaqueous layer three times with ethyl acetate. Dry the combined organiclayers over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel to give the titlecompound: R_(f)=0.5 (silica gel, 1/1 ethyl acetate/hexane). ElementalAnalysis calculated for C₂₃H₂₇Cl₂NO₅: C, 58.97; H, 5.81; N, 2.99; FoundC, 58.85; H, 5.90; N, 2.96.

12.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)piperidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine(0.61 g, 1.3 mmol) and N,N-diisopropylethylamine (0.37 g, 2.86 mmol) inanhydrous dichloromethane (12 mL). Cool the reaction mixture to 0° C.with an ice bath. Slowly add methanesulfonyl chloride (0.19 g, 1.7mmol). After 3.5 hours, dilute the reaction mixture with dichloromethaneand extract with 1M hydrochloric acid and with a saturated solution ofsodium bicarbonate. Dry the organic layer over Na₂SO₄, filter, andconcentrate in vacuo to obtain the title compound: R_(f)=0.60 (silicagel, 1/1 ethyl acetate/hexane).

12.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)piperidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)piperidine(0.71 g, 1.32 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.38 g, 1.32mmol), and N,N-diisopropylethylamine (0.37 g, 2.9 mmol) in acetonitrile(15 mL). Heat to reflux. After 36 hours, partition the residue betweenethyl acetate and saturated aqueous sodium bicarbonate solution. Dry theorganic layer over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 15%methanol/2% triethylamine/ethyl acetate to give the title compound.Elemental Analysis calculated for C₃₉H₄₉Cl₂N₅O₅: C, 63.40; H, 6.68; N,9.48; Found: C, 63.68; H, 6.69; N, 9.57.

PREPARATION 4

Synthesis of 3,4,5-Trimethoxybenzyl mesylate

Combine 3,4,5-trimethoxybenzyl alcohol (9.0 g, 45.4 mmol),N,N-diisopropylethylamine (12.9 g, 100 mmol), and acetonitrile (60 mL).Cool in an ice bath. Add methanesulfonyl chloride (6.76 g, 49.0 mmol).After 2 hours, partition the reaction mixture between water and ethylacetate. Separate the layers and extract the organic layer with 1 Mhydrochloric acid solution and them a saturated solution of sodiumbicarbonate. Dry the organic layer over Na₂SO₄, filter, and evaporate invacuo to give the title compound.

EXAMPLE 13

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine

13.1 Synthesis of 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine

Combine 2-pyrrolidinone (2.85 g, 33.5 mmol) and tetrahydrofuran (70 mL).Cool to −78° C. using a dry-ice/acetone bath. Add a solution ofpotassium bis(trimethylsilyl)amide (67 mL, 0.5 M in toluene, 33.5 mmol).After 45 minutes, add a solution of 3,4,5-trimethoxybenzyl mesylate (8.8g, 32 mmol) in tetrahydrofuran (60 mL). After the addition of3,4,5-trimethoxybenzyl mesylate is complete, heat to reflux. After 18hours, cool the reaction mixture and partition between water and ethylacetate. Separate the aqueous layer and extract 4 times with ethylacetate. Dry the combined organic layers over Na₂SO₄, filter, andconcentrate in vacuo to obtain a residue. Chromatograph the residue onsilica gel eluting with ethyl acetate to give the title compound:R_(f)=0.35 (silica gel, ethyl acetate).

13.2 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-2-oxopyrrolidine

Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (1.0 g, 3.77 mmol)and tetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice/acetonebath. Add a solution of lithium bis(trimet-hylsilyl)amide (4.25 mL, 1 Min THF, 4.52 mmol). After 30 minutes, add a solution of benzyl bromide(0.77 g, 4.52 mmol) in tetrahydrofuran (1 mL). After the addition ofbenzyl bromide is complete, warm slowly to ambient temperature. After 15minutes, add water and extract three times with dichloromethane. Dry thecombined organic layers over Na₂SO₄, filter, and concentrate in vacuo toobtain a residue. Chromatograph the residue on silica gel eluting with1/1 ethyl acetate/hexane to give the title compound: R_(f)=0.69 (silicagel, 1/1 ethyl acetate/hexane).

13.3 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Combine 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-2-oxopyrrolidine(1.0 g, 2.81 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using adry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide(3.09 mL, 1 M in THF, 3.09 mmol). After 30 minutes, add a solution of2-(t-butyldimethylsilyloxy)ethyl bromide (0.74 g, 3.09 mmol) intetrahydrofuran (1 mL). After the addition of2-(t-butyldimethylsilyloxy)ethyl bromide is complete, warm slowly toambient temperature. After 2 hours, add water and extract three timeswith ethyl acetate. Dry the combined organic layers over Na₂SO₄, filter,and concentrate in vacuo to obtain a residue. Chromatograph the residueon silica gel eluting with 1/3 ethyl acetate/hexane to give the titlecompound: R_(f)=0.58 (silica gel, 1/3 ethyl acetate/hexane).

13.4 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine(1.0 g, 1.95 mmol) and tetrahydrofuran (5 mL). Cool to 0° C. using a icebath. Add a solution of tetrabutylammonium fluoride (3.90 mL, 1 M inTHF, 3.90 mmol). After the addition is complete, warm to ambienttemperature. After 1.5 hours, add aqueous 1 M hydrochloric acid solution(20 mL). Extract three times with ethyl acetate. Dry the combinedorganic layers over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane to give the title compound: R_(f)=0.27 (silica gel, 1/1ethyl acetate/hexane).

13.5 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidineto give the title compound.

13.6 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 14

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

14.1 Synthesis of1-(3,4,5-trimethoxybenyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.2 using 4-fluorobenzyl bromide togive the title compound: R_(f)=0.58 (silica gel, 1/1 ethylacetate/hexane).

14.2 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.3 using1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine togive the title compound: R_(f)=0.89 (silica gel, 1/1 ethylacetate/hexane).

14.3 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.4 using1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.22 (silica gel, ethyl acetate).

14.4 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.92 (silica gel, ethyl acetate).

14.5 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine(0.34 g, 0.63 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.35 g, 0.63 mmol), and N,N-diisopropylethylamine (0.33 g, 2.5mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool andpartition the reaction mixture between dichloromethane and a saturatedaqueous ammonium chloride solution. Separate the layers and extract theorganic layer with a saturated aqueous sodium bicarbonate solution. Drythe organic layer over Na₂SO₄, filter, and concentrate in vacuo toobtain a residue. Chromatograph the residue on a short column of silicagel eluting with 2% triethylamine/5% methanol/ethyl acetate to give thetitle compound: R_(f)=0.39 (silica gel, 2% triethylamine/10%methanol/ethyl acetate).

14.6 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidiehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine(0.35 g, 0.51 mmol) and methanol (20 mL). Add a solution of hydrochloricacid (0.26 g, 4 M, 1.02 mmoL) in dioxane. After 18 hours, evaporate thereaction mixture invacuo to give a residue. Triturate the residue withdiethyl ether (100 mL) and stir to give a solid. After 3 hours, decantthe supernatant and add diethyl ether and stir. Repeatedly, decant thesupernatant and add diethyl ether. Decant the supernatant and evaporatein vacuoto give the title compound: mp; 191-194° C.

EXAMPLE 15

1-Benzyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine

15.1 Synthesis of 1-benzyl-3-(phenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.2 using 1-benzyl-2-oxopyrrolidineand benzyl bromide to give the title compound: R_(f)=0.46 (silica gel,1/1 ethyl acetate/hexane)

15.2 Synthesis of1-benzyl-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.3 using1-benzyl-3-(phenylmethyl)-2-oxopyrrolidine to give the title compound:R_(f)=0.35 (silica gel, 1/4 ethyl acetate/hexane).

15.3 Synthesis of1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.4 using1-benzyl-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.40 (silica gel, ethyl acetate).

15.4 Synthesis of1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine to givethe title compound: R_(f)=0.68 (silica gel, ethyl acetate).

15.5 Synthesis of1-benzyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 1.6 using1-benzyl-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimnidazol-2-yl)[1,4]diazepane to givethe title compound.

EXAMPLE 16

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine

16.1 Synthesis of1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine

Combine1-benzyl-3-(phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine(1.19 g, 2.81 mmol) and tetrahydrofuran (20 mL). Cool in an ice bath.Add dropwise a solution of lithium aluminum hydride (2.81 mL, 1 M inTHF, 2.81 mmol). After the addition is complete, warm to ambienttemperature. After 2 hours, heat to reflux. After 1 hour, cool toambient temperature and cautiously add water (0.11 mL), a solution of 1M sodium hydroxide (2.67 mL), and water (0.32 mL). Stir vigorously.After 2 hours, filter through celite and rinse with dichloromethane. Drythe filtrate over Na₂SO₄, filter, and concentrate invacuo to give aresidue. Chromatograph the residue on silica gel eluting with ethylacetate to give the title compound: R_(f)=0.34 (silica gel, 2%triethylamine/30% methanol/ethyl acetate)

16.2 Synthesis of 3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 1-benzyl-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (0.72 g,2.45 mmol) and methanol (20 mL). Add 20% palladium hydroxide-on-carbon(0.231 g). Hydrogenate in a Parr apparatus at an initial pressure of 50psi. After 24 hours, filter through celite, rinse with methanol.Evaporate the filtrate in vacuo to give the title compound: R_(f)=0.01(silica gel, 2% triethylamine/methanol).

16.3 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidine (3.94 mmol) andsodium carbonate (0.21 g, 2.00 mmol) in 1/1 ethyl acetate/water (50 mL).Cool the reaction mixture to 0° C. with an ice bath. Add3,4,5-trimethoxybenzoyl chloride (0.83 g, 3.58 mmol). Warm to ambienttemperature. After 18 hours, separate the layers and extract the aqueouslayer three times with ethyl acetate. Dry the combined organic layersover Na₂SO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with ethyl acetate togive the title compound: R_(f)=0.0⁹ (silica gel, ethyl acetate).

16.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.54 (silica gel, 1/4 ethylacetate/hexane).

16.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzoyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

EXAMPLE 17

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidine

17.1 Synthesis of 3-cyano-3-(4-methoxyphenyl)pentanedioic acid diethylester

Combine 4-methoxyphenylacetonitrile (200 g, 1.36 mol) andtetrahydrofuran (500 mL). Cool to about −5° C. Add dropwise a solutionof sodium bis(trimethylsi.yl)amide (2900 mL, 1 M in tetrahydrofuran,2.90 mol). When the addition is complete warm the reaction mixture toambient temperature and allow to stir for 1 hour. Transfer the abovesolution via cannula into a cooled (−12° C.) solution of ethylbromoacetate (459.9 g) in tetrahydrofuran (1800 mL) at such a rate thatthe temperature of the reaction mixture does not rise above about 15° C.Allow to stir at ambient temperature. After 18 hours, dilute withdiethyl ether and extract with water, 10% hydrochloric acid solution,and saturated aqueous solution of sodium bicarbonate. Dry the organiclayer over MgSO₄, filter, and concentrate in vacuo to obtain a residue.Distill the residue by bulb-to-bulb distillation to give the titlecompound: bp; 175-185° C. at 1.0 mm Hg.

17.2 Synthesis of (3-(4-methoxyphenyl)-5-oxopyrrolidin-3-yl)acetic acidethyl ester

Prepare by the method of Example 2.2.2 using3-cyano-3-(4-methoxyphenyl)pentanedioic acid diethyl ester to give thetitle compound.

17.3 Synthesis of 3-(4-methoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 2.3 using(3-(4-methoxyphenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester togive the title compound: R_(f)=0.35 (silica gel, 85/10/5dichloromethane/methanol/acetic acid).

17.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-(3-(4-methoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(4-inethoxyphenyl)-3-(2-hydroxyethyl)pyrrolidine (20 mmol) andsodium bicarbonate (8.4 g) in acetone (50 mL)/water (50 mL). Add asolution of 3,4,5-trimethoxybenzoyl chloride (4.6 g, 19.9 mmol) inacetone (50 mL). After 3 hours, extract the reaction mixture three timeswith ethyl acetate. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to give the title compound: R_(f)=0.²⁵ (silica gel,6% methanol/dichloromethane).

17.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.44 (silica gel, ethyl acetate).

17.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(4-methoxyphenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.94 g, 1.90 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.52 g, 1.80mmol), and N,N-diisopropylethylamine (0.7 mL, 4.0 mmol) in acetonitrile(30 mL). Heat to reflux. After 18 hours, cool and dilute the reactionmixture ethyl acetate (300 mL). Extract three times with an aqueous 1%sodium bicarbonate solution, and then brine. Dry the organic layer overNa₂SO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with 25% methanol/ethylacetate containing concentrated ammonium hydroxide (20 mL/3L). Evaporatethe product containing fractions in vacuo to give a residue. Dissolvethe residue in dichloromethane, filter, and evaporate in vacuo to give athe title compound: R_(f)=0.20 (silica gel, 20% methanol/ethyl acetate).

17.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidinefumaric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenyl)pyrrolidine(0.53 g) and ethyl acetate (50 mL). Add a solution of fumaric acid (0.17g) in methanol (5 mL). Add diethyl ether (200 mL) and stir. After 18hours, evaporate in vacuo to give a residue. Triturate the residue withdiethyl ether and stir to give a solid. Decant the solvent, add diethylether, and stir. After 18 hours, decant the solvent and evaporate invacuo to give the title compound.

EXAMPLE 18

1-(3,4,5-Trimethoxybenzyl)-3-(3-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)propyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

18.1 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-t-butyldimethylsilyloxypropyl)-2-oxopyrrolidine

Prepare by the method of Example 13.3 using1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine and3-t-butyldimethylsilyloxypropyl iodide to give the title compound:R_(f)=0.52 (silica gel, 1/4 ethyl acetate/hexane).

18.2 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-hydroxypropyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-(t-butyldimethylsilyloxy)propyl)-2-oxopyrrolidine(1.08 mmol) and ammonium fluoride (0.24 g, 6.48 mmol) in methanol (10mL). Heat to reflux. After 2 hours, cool to ambient temperature and pourthe reaction mixture into a brine (30 mL). Extract five times withdichloromethane. Dry the combined organic layers over Na₂SO₄, filter,and concentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with ethyl acetate to give the title compound:R_(f)=0.30 (silica gel, ethyl acetate).

18.3 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-hydroxypropyl)-2-oxopyrrolidine(2.6 mmol), and dichloromethane (15 mL). Cool to −5° C. using a salt-icebath. Add dropwise, methanesulfonyl chloride (0.19 g, 1.62 mmol) at sucha rate as to maintain the reaction temperature below 0° C. After 1 hour,the reaction mixture is extracted with 1 M hydrochloric acid solutionand then a 5% sodium bicarbonate solution. Dry the organic layer overNa₂SO₄, filter, and evaporate in vacuo to give the title compound:R_(f)=0.71 (silica gel, ethyl acetate).

18.4 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(3-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)propyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound: R_(f)=0.39 (silica gel, 2%triethylamine/20%methanol/ethyl acetate).

EXAMPLE 19

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

19.1.1 Synthesis of 3-cyano-3-(4-fluorophenyl)pentanedioic acid diethylester

Prepare by the method of Example 17.1 using 4-fluorophenylacetonitrileto give the title compound.

19.1.2 Synthesis of 3-cyano-3-(4-fluorophenyl)pentanedioic acid diethylester

Prepare by the method of Example 6.1.2 using 4-fluorophenylacetonitrileto give, after recrystallization prom diethyl ether, the title compound.

19.2 Synthesis of (3-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)acetic acidethyl ester

Prepare by the method of Example 2.2.2 using3-cyano-3-(4-fluorophenyl)pentanedioic acid diethyl ester to give thetitle compound.

19.3 Synthesis of 3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 2.3 using(3-(4-fluorophenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester to givethe title compound: R_(f)=0.10 (silica gel, 90/10/10dichloromethane/methanol/acetic acid).

19.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine 3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (4.0 g, 19mmol) and sodium bicarbonate (8.0 g, 95 mmol) in acetone (50 mL) andwater (50 mL). Add a solution of 3,4,5-trimethoxybenzoyl chloride (4.4g, 19.0 mmol) in acetone (50 mL). After 3 hours, extract the reactionmixture three times with ethyl acetate. Dry the organic layer overMgSO₄, filter, and concentrate in vacuo to give the title compound:R_(f)=0.41 (silica gel, 6% methanol/dichloromethane).

19.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.31 (silica gel, ethyl acetate).

19.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.62 g, 1.4 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.5 g, 1.7mmol), and N,N-diisopropylethylamine (0.39 g, 3.0 mmol) in acetonitrile(10 mL). Heat to reflux. After 2 days, cool evaporate in vacuo to obtaina residue. Chromatograph the residue on silica gel eluting with 2%triethylamine/20% methanol/ethyl acetate to give a residue. Dissolve theresidue in dichloromethane, extract with brine, dry the organic layerover Na₂SO₄, filter, and evaporate in vacuo to give the title compound:R_(f)=0.36 (silica gel, 2% triethylamine/30% methanol/ethyl acetate).

19.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidinemaleic acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine(0.41 g) and maleic acid (0.12 g, 1.03 mmol) in ethyl acetate (5 mL) andheat to reflux. After 1 hour, cool to ambient temperature. After 18hours, evaporate in vacuo to give a residue. Triturate the residue withdiethyl ether (15 mL) and stir to give a solid. Collect the solid byfiltration, rinse with diethyl ether, and dry in vacuo to give the titlecompound.

EXAMPLE 20

1-(2-Methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

20.1 Synthesis of 1-(2-methoxybenzyl)-2-oxopyrrolidine

Prepare by the method of Example 13.1 using 2-methoxybenzyl chloride togive the title compound: R_(f)=0.55 (silica gel, 1/1 ethylacetate/hexane).

20.2 Synthesis of1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.2 using 4-fluorobenzyl bromide togive the title compound: R_(f)=0.54 (silica gel, 1/1 ethylacetate/hexane).

20.3 Synthesis of1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.3 using1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine to givethe title compound: R_(f)=0.89 (silica gel, 1/1 ethyl acetate/hexane).

20.4 Synthesis of1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.28 (silica gel, ethyl acetate).

20.5 Synthesis of1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.45 (silica gel, 1/4 ethylacetate/hexane).

20.6 Synthesis of1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-flluorophenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 1.6 using1-(2-methoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 21

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-2-oxopyrrolidine

21.1 Synthesis of methyl 3-cyano-2-phenylpropionate

Combine methyl phenylacetate (2.0 g, 13.3 mmol) and tetrahydrofuran (15mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of lithiumdiisopropylamide (6.66 mL, 2 M in THF, 13.32 mmol). After 1 hour, addα-bromoacetonitrile (1.6 g, 13.3 mmol). After 2 hours, warm the reactionmixture to ambient temperature and partition the reaction mixturebetween ethyl acetate and water. Separate the aqueous layer and extractthree times with ethyl acetate. Dry the combined organic layers overNa₂SO₄, filter, and concentrate in vacuo to obtain a residue. Distillthe residue bulb-to-bulb to give the title compound: bp; 150° C. at 0.5mm Hg; R_(f)=0.72 (silica gel, 25% ethyl acetate/hexane).

21.2 Synthesis of 3-phenyl-2-oxopyrrolidine

Prepare by the method of Example 2.2.2 using methyl3-cyano-2-phenylpropionate to give the title compound R_(f)=0.20 (silicagel, ethyl acetate).

21.3 Synthesis of 1-(3,4,5-trimethoxybenzyl)-3-phenyl-2-oxopyrrolidine

Prepare by the method of Example 13.1 using 3-phenyl-2-oxopyrrolidine togive the title compound R_(f)=0.24 (silica gel, 1/1 ethylacetate/hexane).

21.4 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-3-phenyl-2-oxopyrrolidine

Prepare by the method of Example 13.3 using1-(3,4,5-trimethoxybenzyl)-3-phenyl-2-oxopyrrolidine to give the titlecompound: R_(f)=0.66 (silica gel, 1/1 ethyl acetate/hexane).

21.5 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-phenyl-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-3-phenyl-2-oxopyrrolidineto give the title compound: R_(f)=0.55 (silica gel, ethyl acetate).

21.6 Synthesis of 1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxethyl)-3-phenyl-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-phenyl-2-oxopyrrolidineto give the title compound: R_(f)=0.74 (silica gel, ethyl acetate).

21.7 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenyl-2-oxopyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-phenyl-2-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 22

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine

22.1.1 Synthesis of 3-cyano-3-(3,4-difluorophenyl)pentanedioic aciddiethyl ester

Prepare by the method of Example 3.1.2 using3,4-difluorophenylacetonitrile to give the title compound.

22.1.2 Synthesis of 3-cyano-3-(3,4-difluorophenyl)pentanedioic aciddiethyl ester

Prepare by the method of Example 6.1.2 using3,4-difluorophenylacetonitrile to give the title compound.

22.2.1 Synthesis of (3-(3,4-difluorophenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Prepare by the method of Example 2.2.2 using3-cyano-3-(3,4-difluorophenyl)pentanedioic acid diethyl ester to givethe title compound.

22.2.2 Synthesis of (3-(3,4-difluorophenyl)-5-oxopyrrolidin-3-yl)aceticacid ethyl ester

Combine 3-cyano-3-(3,4-difluorophenyl)pentanedioic acid diethyl ester(106 g, 326 mmol), ethanol (3 L), concentrated aqueous ammonia (160 mL),and Raney nickel (100 g). Hydrogenate at about 50° C. and 200 psi in anautoclave. After 22 hours, filter through celite and rinse the solidswith ethanol. Evaporate the filtrate in vacuo to give a residue.Triturate the residue with ethyl acetate/hexane to give the titlecompound.

22.3 Synthesis of 3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 2.3 using(3-(3,4-difluorophenyl)-5-oxopyrrolidin-3-yl)acetic acid ethyl ester togive the title compound: R_(f)=0.26 (silica gel, 85/10/5dichloromethane/methanol/acetic acid).

22.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-(3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 7.4 using3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine to give the titlecompound: R_(f)=0.25 (silica gel, ethyl acetate).

22.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.44 (silica gel, ethyl acetate).

22.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.37 g, 1.6 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.43 g, 0.8 mmol), and N,N-diisopropylethylamine (0.41 g, 3.2mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool andconcentrate in vacuo to obtain a residue. Chromatograph the residue onsilica gel eluting with 2% triethylamine/10% methanol/ethyl acetate togive the title compound: R_(f)=0.³6 (silica gel, 2% triethylamine/10%methanol/ethyl acetate).

22.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidinefumaric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine(0.57 g) and fumaric acid (0.19 g, 1.64 mmol) in ethyl acetate (20 mL)and heat to reflux. After 2 hours, cool to ambient temperature and stirto give a solid. After 18 hours, decant the solvent and repeatedly adddiethyl ether, stir, and decant. Collect the solid by filtration togive, after drying in vacuo, the title compound.

PREPARATION 4

Synthesis of 4-Methoxybenzyl mesylate

Combine 4-methoxybenzyl alcohol (45.4 mmol), N,N-diisopropylethylamine(12.9 g, 100 mmol), and acetonitrile (60 mL). Cool in an ice bath. Addmethanesulfonyl chloride (6.76 , 49.0 mmol). After 2 hours, partitionthe reaction mixture between water and ethyl acetate. Separate thelayers and extract the organic layer with 1 M hydrochloric acid solutionand then a saturated solution of sodium bicarbonate. Dry the organiclayer over Na₂SO₄, filter, and evaporate in vacuo to give the titlecompound.

EXAMPLE 23

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenylmethyl)-2-oxopyrrolidine

23.1 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.:3 using1-iodo-2-t-butyldimethylsilyloxyethane to give the title compound.

23.2 Synthesis of1-(3,4,5-trimethoxybenyl)-3-(4-methoxyphenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Prepare by the method of Example 13.3 using 4-methoxybenzyl mesylate and1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.15 (silica gel, 1/4 ethylacetate/hexane).

23.3 Synthesis of1-(3,4,5-trimethoxybenzyl-3-4-methoxyphenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.33 (silica gel, ethyl acetate).

23.4 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.53 (silica gel, ethyl acetate).

23.5 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-methoxyphenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzyl)-3-(4-methoxyphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 24

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine

24.1 Synthesis of2-(2-(t-butyldimethylsilyloxy)ethyl)-3-3-phenylpropionitrile

Combine 3-phenylpropionitrile (2.0 g, 15.25 mmol) and tetrahydrofuran(15 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution oflithium bis(trimethylsilyl)amide (16.0 mL, 1 M in THF, 16.0 mmol). After1 hour, add 2-(t-butyldimethylsilyloxy)ethyl iodide (4.58 g, 16.0 mmol).After the addition of 2-(t-butyldimethylsilyloxy)ethyl iodide iscomplete, warm slowly to ambient temperature over about 7 hours. Addwater and extract twice with ethyl acetate. Dry the combined organiclayers over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 5% ethylacetate/hexane to give the title compound: R_(f)=0.50 (silica gel, 10%ethyl acetate/hexane).

24.2 Synthesis of2-(2-(t-butyldimethylsilyloxy)ethyl)-2-allyl-3-phenylpropionitrile

Combine 2-(2-(t-butyldimethylsilyloxy)ethyl)-3-phenylpropionitrile (1.32g, 4.55 mmol) and tetrahydrofuran (8 mL). Cool to −78° C. using adry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide(9.1 mL, 1 M in THF, 9.1 mmol). After 30 minutes, addhexamethylphosphoramide (0.25 mL) and allyl bromide (1.10 g, 9.1 mmol).Warm slowly to ambient temperature. After 12 hours, add water andseparate the layers. Extract the aqueous layer three times with ethylacetate. Combine the organic layers and extract with aqueous 1 Mhydrochloric acid solution. Dry the combined organic layers over Na₂SO₄,filter, and concentrate in vacuo to obtain a residue. Chromatograph theresidue on silica gel eluting with 5% -ethyl acetate/hexane to give thetitle compound: R_(f)=0.83 -(silica gel, 1,/4 ethyl acetate/hexane).

24.3 Synthesis of2-(2-hydroxyethyl)-2-carbomethyloxymethyl-3-phenylpropionitrile

Combine2-(2-(t-butyldimethylsilyloxy)ethyl)-2-allyl-3-phenylpropionitrile (1.19g) and dichloromethane (25 mL) and water (25 mL). Add tetrabutylammonium bromide (0.01 g) and acetic acid (8.0 mL). Add potassiumpermanganate (2.24 g) portionwise over 2 hours. After 18 hours, addsodium sulfite to dissolve the precipitated manganese dioxide. Separatethe layers and adjust the pH of the aqueous layer to about 2 usingaqueous 1 M hydrochloric acid solution. Extract the aqueous layer threetimes with dichloromethane. Dry the combined organic layers over Na₂SO₄,filter, and concentrate in vacuo to obtain a residue. Chromatograph theresidue on silica gel eluting with 1/1 ethyl acetate/hexane to give4-cyano-4-phenylmethyl-δ-valerolactone.

Combine 4-cyano-4-phenylmethyl-δ-valerolactone (0.52 g), methanol (20mL), and sulfuric acid (2 drops). Heat to reflux. After 2 days, addsodium bicarbonate (about 1 g) and stir, filter and evaporate in vacuoto give the title compound. R_(f)=0.28 (silica gel, ethyl acetate).

24.4 Synthesis of2-(2-(t-butyldimethylsilyloxy)ethyl)-2-carbomethyloxymethyl-3-phenylpropionitrile

Combine t-butyldimethylsilyl chloride (2.5 mmol), imidazole (5 mmol),and dimethylformamide (5 mL). Cool to 0° C. in an ice bath. Add asolution of2-(2-hydroxyethyl)-2-carbomethyloxymethyl-3-phenylpropionitrile (0.54 g,2.28 mmol) in dimethylformamide (5 mL). Warm to ambient temperature.After 12 hours, dilute the reaction mixture with hexane (100 mL) andethyl acetate (10 mL). Extract with aqueous 1 M hydrochloric acidsolution and aqueous 5% sodium bicarbonate solution. Dry the organiclayer over Na₂SO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with 1/4 ethylacetate/hexane to give the title compound: R_(f)=0.65 (silica gel, 1/1ethyl acetate/hexane).

24.5 Synthesis of3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine

Combine2-(2-(t-butyldimethylsilyloxy)ethyl)-2-carbomethyloxymethyl-3-phenylpropionitrile(0.26 g, 0.72 mmol) and 10% aqueous concentrated ammoniasolution/ethanol (20 mL) in a Parr bottle. After rinsing with water andethanol, add Raney nickel (2.21 g). Hydrogenate at 50 psi for 24 h.Filter through a celite pad and rinse the solids with ethanol. Evaporatethe filtrate in vacuo to obtain a residue. Partition the residue betweendichloromethane and water. Extract the aqueous layer withdichloromethane. Dry the combined organic layers over Na₂SO₄, filter,and concentrate in vacuo to obtain a residue. Chromatograph the residueon silica gel eluting with 1/1 ethyl acetate/hexane to give the titlecompound: R_(f)=0.11 (silica gel, 1/1 ethyl acetate/hexane).

24.6 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine

Combine3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine(0.13 g, 0.38 mmol) and tetrahydrofuran (2 mL). Cool to −78° C. using adry-ice/acetone bath. Add a solution of potassiumbis(trimethylsilyl)amide (0.76 mL, 0.5 M in toluene, 0.38 mmol). After30 minutes, add a solution of 3,4,5-trimethoxybenzyl chloride (0.08 g,0.38 mmol) in tetrahydrofuran (1 mL). Warm to ambient temperature andadd tetrabutylammonium bromide (0.01 g). Heat to reflux. After 12 hours,cool the reaction mixture and partition between water and ethyl acetate.Separate the aqueous layer and extract twice with ethyl acetate. Dry thecombined organic layers over Na₂SO₄, filter, and concentrate in vacuo toobtain a residue. Chromatograph the residue on silica gel eluting with1/4 ethyl acetate/hexane to give the title compound: R_(f)=0.43 (silicagel, 1/1 ethyl acetate/hexane).

24.7 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-(phenylmethyl)-5-oxopyrrolidine

Prepare by the method of Example 18.2 using1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-3-(phenylmethyl)-5-oxopyrrolidineto give the title compound.

24.8 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-(phenylmethyl)-5-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzyl)-3-(2-hydroxyethyl)-3-(phenylmethyl)-5-oxopyrrolidineto give the title compound: R_(f)=0.42 (silica gel, ethyl acetate).

24.9 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(phenylmethyl)-5-oxopyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzyl)-3-(2-methanesulfonyloxyethyl)-3-(phenylmethyl)-5-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 25

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-(trifluoromethyl)phenylmethyl)-2-oxypyrrolidine

25.1 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine

Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine (1.76 g, 6.63 mmol)and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetonebath. Add dropwise a solution of set-butyllithium (5.10 mL, 1.3 M inhexane, 6.63 mmol). After 45 minutes, slowly add a solution of4-(trifluoromethyl)benzyl bromide (1.58 g, 6.63 mmol) in tetrahydrofuran(5 mL). After 5 hours, add water (10 mL) and warm to ambienttemperature. Separate the layers and extract the aqueous layer threetimes with ethyl acetate. Dry the combined organic layers over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 1/1 ethyl acetate/hexane to give thetitle compound: R_(f)=0.35 (silica gel, 1/1 ethyl acetate/hexanes).

25.2 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine(1.55 g, 3.66 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using adry-ice/acetone bath. Add a solution of sec-butyllithium (3.1 mL, 1.3 Min hexane, 4.0 mmol). After 30 minutes, add a solution of1-iodo-2-(t-butyldimethylsilyloxy)ethane (1.15 g, 4.0 mmol) intetrahydrofuran (1 mL). After 2 hours, warm to ambient temperature.After 12 hours, add water (5 mL). Separate the layers and extract theaqueous layer three times with ethyl acetate. Dry the combined organiclayers over Na₂SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 1/4 ethylacetate/hexane to give the title compound: R_(f)=0.79 (silica gel, 1/1ethyl acetate/hexane).

25.3 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine(0.6 g, 1.0 mmol) and ammonium fluoride (0.23 g, 6.2 mmol) to give thetitle compound: R_(f)=0.35 (silica gel, ethyl acetate).

25.4 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzyl)-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine(0.46 g, 0.99 mmol) to give the title compound: R_(f)=0.67 (silica gel,ethyl acetate).

25.5 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-((4-(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyly-3-(4-(trifluoromethyl)phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine(0.54 g, 0.99 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.54 g, 0.99 mmol), and N,N-diisopropylethylamine (0.5 g, 3.94mmol) and acetonitrile (10 mL). Heat to reflux. After 12 hours, cool toambient temperature, dilute with dichloromethane and extract twice withwater. Dry the organic layer over Na₂SO₄, filter, and evaporate in vacuoto give a residue. Chromatograph the residue on silica gel elu.ting with0.5% concentrated aqueous ammonia solution/5% methanol/ethyl acetate togive the title compound: R_(f)=0.34 (silica gel, 0.5% concentratedaqueous ammonia solution/5% methanol/ethyl acetate).

EXAMPLE 26

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine

26.1.1 Resolution of(+)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine hydrochloricacid salt

Combine (R,R)-di-p-anisoyltartaric acid (0.93 g, 2.2 mmol) and aqueous12 M hydrochloric acid solution (0.19 mL, 2.28 mmol) in water/methanol(10 mL)/(10 mL). Heat to reflux. Add dropwise, a solution of3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (1.0 g, 4.4 mmol)in methanol (10 mL). After 15 minutes, slowly cool to ambienttemperature. Filter the solid that forms and rinse with water to give(−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt. [ ]² _(D) ⁰=−25.1 (c=1.02,dimethylsulfoxide). Analysis on HPLC, on an analytical sample of thefree amine obtained by extraction, using a CHIRALPAK AD 25 cm×0.46 cmcolumn eluting with pentane/methanol/triethylamine (80/10/0.1) with aflow rate of 1.0 mL/minute indicates an ienantiomeric excess of 97.8%,(97.8% ee), retention time 19.0 minutes for the3,4,5-trimethoxybenzamide prepared from the (−)-isomer of the(R,R)-di-p-anisoyltartaric acid salt, retention time 12.5 minutes forthe 3,4,5-trimethoxybenzamide prepared from the (+)-isomer of the(R,R)-di-p-anisoyltartaric acid salt.

26.1.2 Resolution of(+)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine hydrochloricacid salt

Combine (R,R)-di-p-anisoyltartaric acid (6.6 g, 15.8 mmol) andwater/methanol (70 mL)/(70 mL). Heat to reflux. Add aqueous 12 Mhydrochloric acid solution (1.31 mL, 15.7 mmol). Add dropwise, asolution of 3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (7.15g, 31.5 mmol) in methanol (70 mL). After 15 minutes, allow to coolslightly and add seed crystals of(−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and then slowly cool to ambienttemperature. Filter the solid that forms. Retain the filtrate which isenriched in the slower eluting isomer. Combine the solid with hotethanol (800 mL), filter, reduce the volume of the solution to about 600mL and slowly cool to ambient temperature to give a solid. Collect thesolid by filtration and dry in vacuo at 82° C. to give(−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt. Analysis on HPLC, on an analyticalsample of the 3,4,5-trimethoxybenzamide derivative using a CHIRALPAK AD25 cm×0.46 cm column eluting with pentane/ethanol/methanol/triethylamine(80/15/5/0.1) with a flow rate of 1.0 mL/minute indicates anenantiomeric excess of greater than 99%, (>99% ee).

26.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 5.2.2 using(−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt.

26.3 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(prepared from (−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.

26.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(preparedfrom (−)-3-(3,4-difluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) to give the title compound.

EXAMPLE 27

1-(3,4,5-Trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-difluorophenylmethyl)-2-oxopyrrolidine

27.1 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Combine 1-(3,4,5-trimethoxybenzyl)-2-oxopyrrolidine and (1.0 g, 3.77mmol) and tetrahydrofuran (5 mL). Cool to −78° C. using adry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide(4.25 mL, 1 M in THF, 4.52 mmol). After 30) minutes, add a solution of1-iodo-2-t-butyldimethylsilyloxyethane (4.52 mmol) in tetrahydrofuran (1mL). After the addition of 1-iodo-2-t-butyldimethylsilyloxyethane iscomplete, warm slowly to ambient temperature. After 15 minutes, addwater and extract three times with dichloromethane. Dry the combinedorganic layers over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane to give the title compound: R_(f)=0.48 (silica gel, 1/1ethyl acetate/hexane).

27.2 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine(0.7 g, 1.66 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using adry-ice/acetone bath. Add a solution of lithium bis(trimethylsilyl)amide(1.66 mL, 1 M in THF, 1.66 mmol). After 30 minutes, add a solution of3,4-difluorobenzyl bromide (0.34 g, 1.66 mmol) in tetrahydrofuran (1mL). After the addition of 3,4-difluorobenzyl bromide is complete, warmslowly to ambient temperature. After 12 hours, add water and extractthree times with ethyl acetate. Dry the combined organic layers overNa₂SO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane to give the title compound: R_(f)=0.48 (silica gel, 1/1ethyl acetate/hexane).

27.3 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine(0.55 g, 1.05 mmol) and ammonium fluoride (0.23 g, 6.33 mmol) to givethe title compound: R_(f)=0.41 (silica gel, 1/1 ethyl acetate/hexane).

27.4 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidineto give the title compound.

27.5 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-diflurorphenylmethyl)-2-oxopyrrolidine

Combine1-(3,4,5-trimethoxybenzyl)-3-(3,4-diflurorphenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.47 g, 0.91),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.49 g, 0.91 mmol), and diisopropylamine (0.47 g, 3.62 mmol) inacetonitrile (10 mL). Heat to reflux. After 12 hours, cool to ambienttemperature, dilute with dichloromethane, and extract with a saturatedaqueous ammonium chloride solution, a saturated aqueous sodiumbicarbonate solution. Dry the organic layer over Na₂SO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 2% triethylamine/5% methanol/ethyl acetate togive the title compound: R_(f)=0.39 (silica gel, 2% triethylamine/5%methanol/ethyl acetate).

27.6 Synthesis of1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-diflurorphenylmethyl)-2-oxopyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-diflurorphenylmethyl)-2-oxopyrrolidine(0.52 g, 0.74) and methanol (25 mL). Add a solution of hydrochloric acid(0.37 mL, 4 M, 1.47 mmol) in dioxane. After 18 hours, evaporate in vacuoto give a residue. Triturate the residue with diethyl ether and stir togive a solid. decant the solvent and add diethyl ether. Decant, collectthe solid by evaporation, and dry to give the title compound: mp;184-188° C.

EXAMPLE 28

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

28.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.05 g, 0.09 mmol) andtetrahydrofuran (4 mL). Cool to −78° C. using a dry-ice /acetone bath.Add dropwise a solution of sec-butyllithium (0.08 mL, 1.3 M, 0.10 mmol).When the addition of sec-butyllithium is complete, warm the reactionmixture to ambient temperature. Add acrylonitrile (0.005 g, 0.10 mmol)and heat the reaction mixture to reflux. After 12 hours, cool, addacrylonitrile (0.01 g, 0.20 mmol), and heat the reaction mixture toreflux. After 12 hours, cool, add water, separate the layers and extractthe aqueous layer twice with ethyl acetate. Combine the organic layers,dry over Na₂SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 0.5% concentratedaqueous ammonia solution/3% methanol/dichloromethane to give the titlecompound: R_(f)=0.47 (silica gel, 0.5% concentrated aqueous ammoniasolution/3% methanol/dichloromethane).

PREPARATION 5

Synthesis of 2-Methylsulfonylethyl mesylate

Combine 2-methylsulfonylethanol (7.7 g, 62 mmol) and dichloromethane (50mL). Cool in an ice bath. Add methanesulfonyl chloride (7.81 g , 68.2mmol). Add N,N-diisopropylethylamine (8.0 g, 62 mmol). After theaddition of N,N-diisopropylethylamine, warm to ambient temperature.After 12 hours, add water and separate the layers. Extract the organic,layer and extract with a saturated aqueous sodium bicarbonate solution.Dry the organic layer over Na₂SO₄, filter and evaporate in vacuo to givethe title compound: mp; 55-57° C.

EXAMPLE 29

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-1,2-methylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

29.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-[4-(1-(2-methylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.05 g, 0.09 mmol) andtetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice/acetone bath.Add dropwise a solution of sec-butyllithium (0.15 mL, 1.3 M, 0.19 mmol).When the addition of sec-butyllithium is complete, add a solution2-methylsulfonylethyl mesylate (0.02 g, 0.10 mmol) in tetrahydrofuran (2mL). Heat the reaction mixture to reflux. After 12 hours, cool, addsec-butyllithium (0.10 mL) and 2-methylsulfonylethyl mesylate (0.02 g,0.10 mmol) and again heat the reaction mixture to reflux. After 12hours, cool, add water, separate the layers and extract the aqueouslayer twice with ethyl acetate. Combine the organic layers, dry overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with 0.5% concentrated aqueous ammoniasolution/5% methanol/dichloromethane to give the title compound:R_(f)=0.38 (silica gel, 0.5% concentrated aqueous ammonia solution/5%methanol/dichloromethane).

EXAMPLE 30

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

30.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.6 g, 1.0 mmol) andtetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath.Add dropwise a solution of sec-butyllithium (1.26 mL, 1.3 M, 1.64 mmol).When the addition of sec-butyllithium is complete, add a solution ethylvinyl sulfone (0.37 g, 3.08 mmol) in tetrahydrofuran (2 mL). Heat thereaction mixture to reflux and seal with a rubber septum. After 18hours, cool, add ethyl vinyl sulfone (0.37 g, 3.08 mmol) and again heatthe reaction mixture to reflux. After 6 hours, cool, add water, separatethe layers and extract the aqueous layer twice with ethyl acetate.Combine the organic layers, dry over Na₂SO₄, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith 0.2% concentrated aqueous ammonia solution/5%methanol/dichloromethane to give the title compound.

30.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.49 g, 0.70 mmol) and methanol (10 mL). Add a solution of hydrochloricacid (0.52 mL, 4 M, 2.09 mmol) in dioxane. After 2.5 hours, evaporate invacuo to give a residue. Triturate the residue with diethyl ether andstir to give a solid. Repeatedly, decant and add diethyl ether, collectthe solid by filtration and dry to give the title compound.

EXAMPLE 31

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

31.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.63 g, 1.07 mmol) andtetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice /acetone bath.Add dropwise a solution of sec-butyllithium (1.23 mL, 1.3 M, 1.61 mmol).When the addition of sec-butyllithium is complete, add a solution phenylvinyl sulfone (0.36 g, 2.14 mmol). Heat the reaction mixture to reflux.After 12 hours, cool, add phenyl vinyl sulfone (0.36 g, 2.14 mmol) andagain heat the reaction mixture to reflux. After 3 hours, cool, addphenyl vinyl sulfone (0.36 g, 2.14 mmol) and again heat the reactionmixture to reflux. After 2.5 hours, cool, add water, separate the layersand extract the aqueous layer twice with ethyl acetate. Combine theorganic layers, dry over Na₂SO₄, filter, and evaporate in vacuo to givea residue. Chromatograph the residue on silica gel eluting with 0.5%concentrated aqueous ammonia solution/5% methanol/dichloromethane togive the title compound.

31.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-phenylsulfonylethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.40 g, 0.53 mmol) and methanol (10 mL). Add a solution of hydrochloricacid (0.4 mL, 4 M, 1.6 mmol) in dioxane. After 2.5 hours, evaporate invacuo to give a residue. Triturate the residue with diethyl ether andstir to give a solid. Repeatedly, decant and add diethyl ether, collectthe solid by filtration and dry to give the title compound.

EXAMPLE 32

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine

32.1 Synthesis of 3-cyano-3-(pyrid-2-yl)-pentanedioic acid diethyl ester

Prepare by the method of Example 1.1 using 2-pyridineacetonitrile togive the title compound: mp; 86.5-88.0° C.; R_(f)=0.46 (silica gel, 1/2ethyl acetate/hexane). Elemental Analysis calculated for C₁₅H₁₈N₂O₄: C,62.06; H, 6.25; N, 9.65; Found: C, 62.23; H, 6.27; N, 9.66.

32.2 Synthesis of (3-(pyrid-2-yl)-5-oxopyrrolidin-3-yl)acetic acid ethylester

Prepare by the method of Example 1.2 using3-cyano-3-(pyrid-2-yl)pentanedioic acid diethyl ester to give the titlecompound: R_(f)=0.31 (silica gel, 20/1 ethyl acetate/methanol).Elemental Analysis calculated for C₂₇H₁₆N₂O₃: C, 62.89; H, 6.50; N,11.28; Found: C, 62.54; H 6.50; N, 11.18.

32.3 Synthesis of 3-(pyrid-2-yl)-3-(2-hydroxyethyl) pyrrolidine

Prepare by the method of Example 1.3 using(3-(pyrid-2-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester to givethe title compound: mp; 50-55° C.

32.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 1.4.1 using3-(pyrid-2-yl)-3-(2-hydroxyethyl)pyrrolidine to give the title compound:mp; 52.0-55.0; R_(f)=0.23 (silica gel, 3% methanol/dichloromethane).Elemental Analysis calculated for C₂₁H₂₆N₂O₅•0.30 H₂O: C, 64.37; H,6.84; N, 7.15; Found: C 64.71; H, 6.87; N, 7.05.

32.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(3-(pyrid-2-yl)-3-(2-oxoethyl)pyrrolidine

Combine oxalyl chloride (0.11 g, 0.83 mmol) with dichloromethane (2 mL)and cool to −60° C. Add dropwise a solution of dimethyl sulfoxide (0.13g, 1.65 mmol) in dichloromethane (0.12 mL) while maintaining thetemperature below −50° C. After addition is complete, stir for 10minutes. Add a solution of1-(3,4,5-trimethoxybenzoyl)-(3-(pyrid-2-yl)-3-(2-hydroxyethyl)pyrrolidine(0.92 g, 0.75 mmol) in dichloromethane (1.5 mL) and stir for 1 hour.Cool the reaction to −78° C. and add dropwise triethylamine (3.75 mmol).Allow the reaction to warm to ambient temperature and stir for 2 hours.Pour the reaction mixture into water. Extract this mixture withdichloromethane. Separate the organic layer and dry over Na₂SO₄, filter,and evaporate in vacuo to give a residue. Chromatograph the residue onsilica gel to give the title compound.

32.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-2-yl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-2-yl)-3-(2-oxoethyl)pyrrolidine(0.29 g, 0.75 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.26 g, 0.91mmol) silica gel (about 2 g) and 3 Å molecular sieves (about 2 g) inmethanol (16 mL). After 18 hours, add sodium cyanoborohydride (0.47 g,7.5 mmol) and stir. After 7 days, add a solution of 2 M sodium hydroxideand dichloromethane. After 1 hour, filter, separate the layers in thefiltrate, dry the organic layer over Na₂SO₄, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith 1/1 methanol/ethyl acetate to give the title compound: mp; 40-42°C. Elemental Analysis calculated for C₃₇H₄₈N₆O₅•0.75 H₂O: C, 66.30; H7.44; N, 12.54; Found: C, 66.33; H, 7.50; N, 12.49.

EXAMPLE 33

(+)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

33.1 Resolution of (+)-3-(4-fluorophenyl)-3-(2-hydroxethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt and(−)-3-(4-fluorophenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt

Combine 3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine (32 mmol) andbutanone (400 mL). Add a solution of (R,R)-di-p-anisoyltartar:ic acid(32 mmol) in butanone (80 mL). Heat to reflux. After 15 minutes, cool toambient temperature and evaporate in vacuo to give a residue. Combinethe residue and butanone (1000 mL) and methanol (430 mL) and heat. Addmethanol (about 100 mL). Slowly cool to ambient temperature to give asolid. After 18 hours, filter the solid. Recrystallize the solid frombutanone/methanol (80 mL/80 mL) to give(−)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt. [α]² _(D) ⁰=−98.9 (c=0.70,methanol). Analysis on HPLC, on an analytical sample of the3,4,5-trimethoxybenzamide derivative, using a CHIRALPAK AD 25 cm×0.46 cmcolumn eluting with pentane/ethanol/methanol/triethylamine(80/15/10/0.1) with a flow rate of 1.0 ml/minute indicates anenantiomeric excess of 99.6%, (99.6% ee), the 3,4,5-trimethoxybenzamideprepared from (−)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt gave a retention time of 23.0minutes, the 3,4,5-trimethoxybenzamide prepared from(+)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt gave a retention time of 15.4minutes.

33.2.1 Synthesis of(+)-1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 8.2.1 using(−)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid to give the title compound.

33.2.2 Synthesis of(+)-1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine (−)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (5.0 g, 8.0 mmol) and sodiumcarbonate (3.39 g, 32 mmol) in ethyl acetate/water (41/, 125 mL). Coolin an ice bath and add a solution of 3,4,5-trimethoxybenzoyl chloride(1.94 g, 8.4 mmol) in ethyl acetate (60 mL). After 2 hours, warm toambient temperature . After 18 hours, separate the layers, and extractthe organic layer twice with a 1 M aqueous hydrochloric acid solution,twice with a saturated aqueous sodium bicarbonate solution, water andthen brine. Dry the organic over Na₂SO₄, filter, and concentrate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith 1/20 methanol/ethyl acetate to give, after drying, the titlecompound: mp; 55-60° C. R_(f)=0.28 (silica gel, 1/20 methanol/ethylacetate). [α]² _(D) ⁰=+36.70 (1.04, chloroform).

33.3 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using(+)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.47 (silica gel, 1/20 methanol/ethylacetate).

33.4 Synthesis of(+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from(+)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine)(0.86 g, 1.8 mmol), N,N-diisopropylethylamine (1.5 mL), and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.0 g, 1.86 mmol) in acetonitrile (50 mL). Heat to reflux. After 2days, dilute the reaction mixture with ethyl acetate (250 mL) andextract with a saturated aqueous sodium bicarbonate solution. Dry theorganic layer over Na₂SO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 25%methanol/ethyl acetate containing concentrated aqueous -ammonia (20mL/:3L) to give the title compound: R_(f)=0.30 (silica gel, 40%methanol/ethyl acetate).

33.5 Synthesis of(+)-1-(3,4,5-trimethoxybenz~oyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidinehydrochloric acid salt

Combine(+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine(0.75 g) and methanol (20 mL). Add a solution of hydrochloric acid (1.5mL, 4 M, 6 mmol) in dioxane. After 24 hours, evaporate in vacuo to givea residue. Dissolve the residue in methanol (about 5 mL) and add diethylether (200 mL) and stir to give a solid. Decant the solvent add diethylether and stir. Decant the solvent and collect the solid to give, afterdrying in vacuo, the title compound. [α]² _(D) ⁰=+5.8° (c=0.86,chloroform).

EXAMPLE 34

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine

34.1.1 Synthesis of 3-cyano-3-(pyrid-3-yl)pentanedioic acid diethylester

Prepare by the method of Example 3.1.2 using 3-pyridineacetonitrile togive the title compound.

34.1.2 Synthesis of 3-cyano-3-(pyrid-3-yl)pentanedioic acid diethylester

Combine 3-pyridineacetonitrile (25 g, 212 mmol) and tetrahydrofuran (200mL). Cool to about −70° C. using a dry-ice/acetone bath. Add dropwise, asolution of sodium bis(trimethylsilyl)amide (435 mL, 1 M intetrahydrofuran, 435 mmol) while maintaining the reaction temperaturebelow about −68° C. When the addition is complete, warm the reactionmixture to ambient temperature and allow to stir for 1 hour. Transferthe above solution via cannula into a cooled (−5° C.) solution of ethylbromoacetate (84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such arate that the temperature of the reaction mixture does not rise aboveabout 15° C. Allow to stir at ambient temperature. After 18 hours,quench with saturated aqueous solution of ammonium chloride andevaporate in vacuo to remove most of the tetrahydrofuran. Extract theevaporated reaction mixture twice with diethyl ether. Dry the organiclayer over MgSO₄, filter, and concentrate in vacuo to obtain a residue.Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane to give the title compound.

34.2.1 Synthesis of (3-(pyrid-3-yl)-5-oxopyrrolidin-3-yl)acetic acidethyl ester

Prepare by the method of Example 1.2 using3-cyano-3-(pyrid-3-yl)pentanedioic acid diethyl ester to give the titlecompound.

34.2.2 Synthesis of (3-(pyrid-3-yl)-5-oxopyrrolidin-3-yl)acetic acidethyl ester

Combine 3-cyano-3-(pyrid-3-yl)pentanedioic acid diethyl ester (50 g, 172mmol) and cobalt(II)chloride hexahydrate (81.8 g, 344 mmol) in methanol(500 mL). While maintaining the temperature at or below 20° C. with anice-bath, add portionwise sodium borohydride (65.1 g, 1.72 mol). Afterthe addition is complete, allow the reaction mixture to stand at ambienttemperature. After 18 hours, evaporate the reaction mixture in vacuo toobtain a residue. Quench the reaction mixture by adding ammoniumchloride and 0.5 M aqueous sodium hydroxide solution. Adjust the pH ofthe quenched reaction mixture to about 8 using 1 M aqueous hydrochloricacid solution. Filter through celite and extract the aqueous filtratetwice with dichloromethane. Combine the organic layers, dry over Na₂SO₄,filter, and concentrate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with dichloromethane/methanol 10/1 to givethe title compound.

34.3.1 Synthesis of 3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 1.3 using3-(pyrid-3-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester to give thetitle compound.

34.3.2 Synthesis of 3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine

Combine lithium aluminum hydride (4.0 g, 105 mmol) and anhydroustetrahydrofuran (200 mL). Slowly, add a solution of3-(pyrid-3-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester (13.0 g,52.4 mmol) in anhydrous tetrahydrofuran (100 mL). After the addition iscomplete, heat to reflux. After 4 hours, cool in an ice-bath. Add water(4 mL) dropwise at such a rate that the temperature of the reactionmixture does not rise above 20° C. Cool to 10° C., add 2 M aqueoussodium hydroxide solution (4.0 mL). Add water (16 mL) and stir. After 16hours, filter the reaction mixture and concentrate the filtrate in vacuoto give an aqueous layer. Extract with dichloromethane and lyophilizethe aqueous layer to give a residue. Combine the residue anddichloromethane and methanol. Filter and evaporate the filtrate in vacuoto give the title compound.

34.3.3 Synthesis of 3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine

Combine lithium aluminum hydride (2.65 g, 70 mmol) and3-(pyrid-3-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester (7.2 g, 35mmol) in anhydrous tetrahydrofuran (100 mL). Heat to reflux. After 12hours, cool the reaction mixture and add lithium aluminum hydride (2.65g, 70 mmol). After 20 hours, cool in an ice-bath. Add water (8 mL)dropwise at such a rate that the temperature of the reaction mixturedoes not rise above 20° C. Cool to 10° C., add 2M aqueous sodiumhydroxide solution (8.0 mL). Add water (16 mL) and stir. After 1 hour,filter the reaction mixture and extract with dichloromethane. Evaporatethe aqueous layer to give a residue. Combine the residue anddichloromethane, filter thorough celite, and evaporate the filtrate invacuo to give the title compound.

34.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 7.4 using3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine to give, afterchromatography on silica gel eluting with dichloromethane/methanol 5/1,the title compound.

34.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl)-3-(2-hydroxyethyl)pyrrolidine(0.45 g, 1.16 mmol) in dichloromethane (6 mL). Cool in an ice bath. Addmethanesulfonyl chloride (0.015 mL, 1.15 mmol) and triethylamine (0.032mL, 1.6 mmol). After 1 hour, dilute the reaction mixture withdichloromethane and extract with brine. Separate the layers and extractthe aqueous layers twice with dichloromethane. Combine the organiclayers. Dry over MgSO₄, filter, and evaporate in vacuo to give the titlecompound.

34.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-3-yl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-3-yl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.54 g, 1.16 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.95 g, 1.74mmol), and N,N-diisopropylethylamine (0.81 mL, 4.64 mmol) inacetonitrile (16 mL). Heat to reflux. After 24 hour, evaporate in vacuo,dilute with dichloromethane, and extract with brine. Dry the organiclayer over Na₂SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 6/1/0.5methanol/ethyl acetate/concentrated aqueous ammonia to give the titlecompound: R_(f)=0.27 (silica gel, 6/1/0.5 methanol/ethylacetate/concentrated aqueous ammonia).

EXAMPLE 35

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

35.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.89, 1.37 mmol) andtetrahydrofuran (50 mL). Cool to 0° C. using ice-bath. Add potassiumhydride (82.5 mg, 2.06 mmol). After 1 hour, add 2-picolyl chloride (175mg, 1.37 mmol). The 2-picolyl chloride is obtained from 2-picolylchloride hydrochloride by treatment with excess sodium bicarbonate indichloromethane, filtration, and evaporation in vacuo. Allow to warm toambient temperature. After 18 hours, add potassium hydride (82.5 mg,2.06 mmol), 2-picolyl chloride (87 mg, 0.68 mmol), and morpholine (0.1mL). After 18 hours, cool to −78° C. and quench with methanol (5 mL)followed by water (15 mL). Warm to ambient temperature and evaporateinvacuo to remove most of the methanol. Extract twice withdichloromethane. Combine the organic layers, dry over Na₂SO₄, filter,and evaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 0.1% concentrated aqueous ammonia solution/10%methanol/dichloromethane to give the title compound: R_(f)=0.30 (silicagel, 0.1% concentrated aqueous ammonia solution/10%methanol/dichloromethane).

35.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-methyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.3 g, 0.43 mmol) and dichloromethane (15 mL). Add a solution ofhydrochloric acid (0.22 mL, 4 M, 0.86 mmol) in dioxane. After 3 hours,evaporate in vacuo to give a residue. Triturate the residue with diethylether to give a solid, collect the solid by filtration and dry to givethe title compound.

EXAMPLE 36

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(thien-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

36.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(thien-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 35.1 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(RrR)-di-p-anisoyltartaric acid salt) and 2-(bromomethyl)thiophene (J.Am. Chem. Soc., 71 1201-1204 (1949)) to give the title compound.

EXAMPLE 37

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

37.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 35.1 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 3-(chloromethyl)furan (J. Am.Chem. Soc. 72, 2195-2199 (1950)) to give the title compound.

EXAMPLE 38

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

38.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 35.1 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 2-(chloromethyl)furan (T.Reichstein et al., Ber., 63 749-754 (1930)) to give the title compound.

EXAMPLE 39

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-oxobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

39.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-oxobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 35.1 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and 1-bromo-butan-2-one to givethe title compound.

EXAMPLE 40

(+)-1-(2,3,4-Trimethoxybenzoyl)-3-(2-(4-(1(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

40.1 Synthesis of1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine 2,3,4-trimethoxybenzoyl chloride (10 mmol) and3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared by extraction from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine R,R-di-p-anisoyltartaric acidsalt) (2.1 g, 9.2 mmol) in acetone (70 mL). Add water (25 mL) andpotassium carbonate (1.93 g, 14 mmol). Dilute the reaction mixture withethyl acetate and extract with aqueous sodium bicarbonate solution andbrine. Dry the organic layer over Na₂SO₄, filter, and evaporate invacuoto give the title compound.

40.2 Synthesis of1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidineR,R-di-p-anisoyltartaric acid salt)(1.01 g, 2.6 mmol) to give the titlecompound.

40.3 Synthesis of1-(2,3,4-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 7.6 using1-(2,3,4-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodicacid salt to give the title compound. [α]² _(D) ⁰=+15.1 (c=0.83,chloroform).

PREPARATION 6

4-(1-(5-Hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane

Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (10mmol) and sodium hydride (10 mmol) in dimethylformamide (20 mL). Aftergas evolution ceases, add ethyl 5-chloromethyl-2-furoate (10 mmol) andstir. After 3 days, evaporate in vacuo to give a residue. Combine theresidue and ethyl acetate. Extract with water and brine. Dry the theorganic layer over Na₂SO₄, filter, and evaporate in vacuo to give1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-ethoxycarbonyl-4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(5 mmol) and lithium aluminum hydride (5 mmol) in tetrahydrofuran. Heatto reflux. After 12 hour, cool and carefully quench the reaction mixturewith 10% aqueous ammonium chloride solution. Extract the reactionmixture with ethyl acetate. Dry the the organic layer over Na₂SO₄,filter, and evaporate in vacuo to give1-ethoxycarbonyl-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-ethoxycarbonyl-4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(4 mmol) and sodium hydroxide (8 mmol) in isopropanol (20 mL). Heat toreflux. After 2 days, evaporate the reaction mixture in vacuo to give aresidue. Combine the residue and ethyl acetate. Extract with water andbrine. Dry the organic layer over Na₂SO₄, filter, and evaporate in vacuoto give the title compound.

Alternately, combine 2-chlorobenzimidazole (20 mmol) and sodium hydride(20 mmol) in dimethylformamidle (30 mL). After gas evolution ceases, addethyl 5-chloromethyl-2-furoate (20 mmol) and stir. After 1 day,evaporate in vacuo to give a residue. Combine the residue and ethylacetate. Extract with water and brine. Dry the the organic layer overNa₂SO₄, filter, and evaporate in vacuo to give1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole.

Combine 1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-2-chloro-1H-benzimidazole(10 mmol), [1,4]diazepane (10 mmol), and1,8-diazabicyclo[5.4.0]undec-7-ene (1.8 mL) in pyridine (20 mL). Heat toreflux. After 2 days, evaporate in vacuo to give a residue. Combine theresidue and ethyl acetate. Extract with water and brine. Dry the theorganic layer over Na₂SO₄, filter, and evaporate in vacuo to give4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(10 mmol) and lithium aluminum hydride (10 mmol) in tetrahydrofuran.Heat to reflux. After 12 hour, cool and carefully quench the reactionmixture with water (0.4 mL), 15% aqueous sodium hydroxide solution (0.4mL) and water (1.2 mL). Filter and extract the filtrate with ethylacetate. Dry the the organic layer over Na₂SO₄, filter, and evaporate invacuo to give the title compound.

Alternatively, combine4-(1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(1.0 g, 2.7 mmol) and tetrahydrofuran (10 mL). Add a solution of lithiumaluminum hydride in tetrahydrofuran (2.7 mL, 1 M, 2.7 mmol). After 18hour, quench by slow portionwise addition of Glauber's salt (Na₂SO₄•10H₂O) until gas evolution ceases. Add dichloromethane (20 mL) and celiteand stir. Filter and evaporate in vacuo to give the title compound.

EXAMPLE 41

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

41.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 1.6 using1-(3,4,5-trimethoxybenzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneto give, after chromatography on silica gel eluting with methanol, thetitle compound: R_(f)=0.41 (silica gel, methanol).

41.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidiazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineHydrochloride salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.47 g, 0.68 mmol) and methanol (10 ml). Add a solution of hydrochloricacid in dioxane (0.17 mL, 4M, 0.68 mmol). After 18 hours, evaporate invacuo to give a residue. Triturate the residue with diethyl ether togive a solid. Repeatedly, decant solvent and add diethyl ether. Collectthe solid by filtration to give the title compound.

EXAMPLE 42

1-(2,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

42.1 Synthesis of1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-2-hydroxyethyl)pyrrolidine

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (1.8 mmol) and sodiumcarbonate (0.76 g, 7.2 mmol) in ethyl acetate/water (10 mL/10 mL). Withstirring, add a solution of 2,4,5-trimethoxybenzoyl chloride (1.1 g, 1.8mmol) in ethyl acetate (1 mL). After 18 hours, separate the layers andextract the aqueous layer twice with ethyl acetate. Combine the organiclayers, dry over Na₂SO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 9/1 ethylacetate/ethanol to give the title compound.

42.2 Synthesis of1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.33g, 0.81 mmol) to give the title compound.

42.3 Synthesis of1-(2,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 7.6 using1-(2,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt to give the title compound: R_(f)=0.42 (silica gel,9/1/0/1 dichloromethane/methanol/concentrated aqueous ammonia).

PREPARATION 7

4-(1-(2-Hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydrochloricacid salt

Combine 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (5.10g, 1.8 mmol) and 48% hydrobromic acid (25 mL). Heat to reflux. After 18hours, dilute with water and adjust the pH to 12 using aqueous 5 Msodium hydroxide solution. Extract three times with dichloromethane. Drythe combined organic layers over Na₂SO₄, filter, and evaporate in vacuoto give a residue. Combine the residue and methanol (50 mL). Add asolution of hydrochloric acid (5.0 mL, 4 M, 20 mmol) in dioxane.Evaporate in vacuo to give a residue. Triturate the residue with diethylether to give a solid. Collect the solid by filtration and dry to givethe title compound.

EXAMPLE 43

(+)-1-3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

43.1 Synthesis of(+)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.3 g, 1.2 mmol),4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydrochloricacid salt (0.52 g, 1.12 mmol), potassium iodide (0.2 g), andN,N-diisopropylethylamine (0.4 g, 4 mmol) in acetonitrile (20 mL). Heatto reflux. After 18 hours, cool and dilute the reaction mixture ethylacetate. Extract three times with a half saturated aqueous sodiumbicarbonate solution, and then brine. Dry the organic layer over Na₂SO₄,filter, and concentrate invacuo to obtain a residue. Chromatograph theresidue on silica gel eluting with 40% methanol/ethyl acetate/1%concentrated aqueous ammonia solution to give, after drying invacuo at70° C., the title compound: mp; 73-78° C. [α]² _(D) ⁰=+7.7° (c=1.04,methanol). R_(f)=0.23 (silica gel, 40% methanol/ethyl acteate).

PREPARATION 8

4-(1-(2-Cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHydriodic acid salt

Combine 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (5.95g, 20.6 mmol) and 48% hydrobromic acid (50 mL). Heat to reflux. After3.5 hours, cool the reaction mixture and dilute with a solution ofsodium hydroxide (23 g, 0.57 mmol) in water (250 mL). Extract threetimes with dichloromethane. Combine the aqueous layer, dichloromethane(200 mL), and sodium chloride (50 g) and stir. After 18 hours, separatethe layers and combine all the organic layers, dry over Na₂SO₄, filter,and evaporate in vacuo to give4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine 4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (1.30g, 5.0 mmol), tetrahydrofuran (40 mL), and water (10 mL). Add dropwise asolution of di-t-butyl dicarbonate (1.09 g, 5.0 mmol) in tetrahydrofuran(15 mL). After 18 hours, concentrate the reaction mixture in vacuo toremove most of the tetrahydrofuran and combine the concentrated reactionmixture with dichloromethane. Separate the layers, dry over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with ethyl acetate to give1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.25 (silica gel, ethyl acetate).

Alternately, combine4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (4.9 g, 18.8mmol) and dichloromethane (120 mL). Add dropwise a solution ofdi-t-butyl dicarbonate (4.31 g, 19.7 mmol) in dichloromethane (20 mL).After 72 hours, concentrate the reaction mixture in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with ethylacetate to give upon standing1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:mp: 108-112° C. R_(f)=0.25 (silica gel, ethyl acetate).

Combine1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(1.7 g, 4.7 mmol), tetrahydrofuran (70 mL), and dimethylformamide (8mL). Cool in an ice bath. Add with stirring, sodium hydride (0.28 g, 60%in oil, 7.0 mmol). After 3 hours, warm to ambient temperature. After 30minutes, again cool in an ice bath and add bromoacetonitrile (1.12 g,9.36 mmol). Warm to ambient temperature. After 18 hours, again cool inan ice bath and add a saturated aqueous solution of ammonium chloride (5mL) and then water (5 mL). Concentrate the reaction mixture in vacuo toremove most to the tetrahydrofuran and dilute with dichloromethane (150mL). Extract three times with water, dry the organic layer over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with ethyl acetate to give1-(t-butoxycarbonyl)-4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.38 (silica gel, ethyl acetate).

Combine1-(t-butoxycarbonyl)-4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.36 g, 0.91 mmol), dichloromethane (15 mL), and methanol (5 mL). Coolin an ice bath and add hydriodic acid (0.25 mL, 57%, 1.86 mmol). Warm toambient temperature. After 5 hours, concentrate the reaction mixture invacuo to give a residue. Combine the residue and diethyl ether (40 mL)and stir. After 18 hours, decant the solvent, add diethyl ether, andstir to give a solid. Collect the solid by filtration and dry to givethe title compound.

EXAMPLE 44

1-(3,4,5-Trimethoxybenzoyl-3-(2-(4-(1-(2-cyanomethoxyethyl)-1H-benzimidazol-2-y)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

44.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.62 g, 1.34 mmol),4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt (0.67 g, 1.22 mmol), and N,N-diisopropylethylamine(0.8 mL, 4.6 mmol) in acetonitrile (15 mL). Heat to reflux. After 40hours, cool and dilute the reaction mixture with ethyl acetate, Extractwith a saturated aqueous sodium bicarbonate solution, and then brine.Dry the organic layer over Na₂SO₄, filter, and concentrate inveacuo toobtain a residue. Chromatograph the residue on silica gel eluting with5% methanol/dichloromethane/1% concentrated aqueous ammonia solution togive, after drying, the title compound: R_(f)=0.20 (silica gel, 5%methanol/dichloromethane/1% concentrated aqueous ammonia solution)

44.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanomethyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.31 g, 0.46 mmol) and dichloromethane (15 mL). Cool in an ice bath andadd a solution of hydrochloric acid in dioxane (0.23 ml, 4 M, 0.94mmol). Warm to ambient temperature. After 18 hours, concentrate thereaction mixture in vacuo to give a residue. Combine the residue anddiethyl ether (150 mL) and stir. After 18 hours, decant the solvent, adddiethyl ether, and stir to give a solid. Collect the solid by filtrationand dry to give the title compound; mp: 134-148° C.

PREPARATION 9

4-(1-(4-Oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic acidsalt

Combine 4-(1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (6.5g, 25.4 mmol), tetrahydrofuran (130 mL), and water (40 mL). Add sodiumbicarbonate (4.26 g, 50.7 mmol) and cool in an ice bath. Add dropwise asolution of di-t-butyl dicarbonate (5.54 g, 25.4 mmol) intetrahydrofuran (20 mL). Warm to ambient temperature. After 18 hours,concentrate the reaction mixture in vacuo to remove most of thetetrahydrofuran and combine the concentrated reaction mixture withdichloromethane. Extract with water and then brine. Dry the organiclayer over Na₂SO₄, filter, and evaporate in vacuo to give1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp:225-226° C. R_(f)=0.28 (silica gel, 5% methanol/dichloromethane/1%saturated aqueous ammonia solution).

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane(1.10 g, 3.5 mmol) and tetrahydrofuran (45 mL) and dimethylformamide (5mL). Cool in an ice bath and add sodium hydride (0.21 g, 60% in oil,5.22 mmol). After 1 hour, add 5-chloropentan-2-one, ethylene ketal (0.79mL, 5.22 mmol) and tetra-n-butylammonium bromide (112 mg, 0.35 mmol) andwarm to ambient temperature. Heat to reflux. After 18 hours, cool, addsodium hydride (0.1 g) and 5-chloropentan-2-one, ethylene ketal (0.50mL) and again heat to reflux. After 24 hours, cool in a dry-ice/acetonebath and add a saturated aqueous solution of ammonium chloride. Warm toambient temperature and dilute the reaction mixture with a saturatedaqueous solution of sodium bicarbonate. Concentrate in vacuo to removemost to the tetrahydrofuran and extract three times with ethyl acetate.Extract the combined organic layers with water and then brine, dry theorganic layer over Na₂SO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 5%methanol/dichloromethane/0.1% saturated aqueous ammonia solution to give1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane,ethylene ketal: R_(f)=0.47 (silica gel, 5% methanol/dichloromethane/0.1%saturated aqueous ammonia solution).

Combine1-(t-butoxycarbonyl)-4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane,ethylene ketal (0.9 g, 2.0 mmol) and dichloromethane (20 mL). Cool in anice bath and add hydriodic acid (0.53 mL, 57%, 4.05 mmol). Warm toambient temperature. After 0.5 hours, add water (0.5 mL) and heat toreflux. After 18 hours, cool to ambient temperature and evaporate invacuo to give a residue. Combine the residue and methanol (45 mL) andadd diethyl ether (250 mL) with stirring to give a solid. After 30minutes, collect the solid by filtration to give, after drying the titlecompound. Elemental Analysis calculated for C₁₇H₂₄N₄O•2HI: C, 36.71; H,4.71; N, 10.07; Found: C 36.94; H, 4.47; N, 9.84.

EXAMPLE 45

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)-[1,4diazepanyl)ethyl)-3-phenylpyrrolidine

45.1 Synthesis of1-3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.40 g, 0.72 mmol),4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.30 g, 0.65 mmol), and N,N-diisopropylethylamine (0.52 mL, 3.02mmol) in acetonitrile (10 mL). Heat to reflux. After 24 hours, cool andpartition the reaction mixture between ethyl acetate and a halfsaturated aqueous sodium bicarbonate solution. Separate the organiclayer extract with a saturated aqueous sodium bicarbonate solution andthen brine. Dry the organic layer over Na₂SO₄, filter, and concentratein vacuo to obtain a residue. Chromatograph the residue on silica geleluting with 10% methanol/dichloromethane/0.1% concentrated aqueousammonia solution to give the title compound: R_(f)=0.45 (silica gel, 10%methanol/dichloromethane/0.1% concentrated aqueous ammonia solution).

45.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-oxopentyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.34 g, 0.5 mmol) and dichloromethane (5 mL). Cool in an ice bath andadd a solution of hydrochloric acid in dioxane (0.15 ml, 4 M, 0.6 mmol).Warm to ambient temperature. After 20 minutes, add diethyl ether (80 mL)and stir to give a solid. Collect the solid by filtration and dry togive the title compound: mp; 95-112° C.

PREPARATION 10

1-(t-Butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane

Combine 1-ethoxycarbonyl[1,4]diazepane (18.0 g, 104 mmol) and2-chlorobenzimidazole (7.93 g, 52 mmol). Heat to 130° C. After 4 hours,cool to ambient temperature and add hot methanol to dissolve thereaction mixture. Add a saturated aqueous solution of sodium bicarbonate(150 mL) and concentrate in vacuo to remove most of the methanol.Combine the aqueous reaction mixture and 95/5 diethyl ether/ethylacetate. Separate the aqueous layer and extract three times withdichloromethane. Combine the dichloromethane layers, dry over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Triturate the residuewith ethyl acetate (100 mL) to give a solid. Chromatograph on silica geleluting with 10% methanol/dichloromethane/0.1% concentrated aqueousammonia to give a residue. Triturate that residue with 9/1 diethylether/ethyl acetate to give a solid. Collect solid by filtration and dryin vacuo to give1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane: mp; 161-162° C.

Combine 1-ethoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (5.22 g,18.1 mmol) and aqueous 48% hydrobromic acid solution (25 mL). Heat toreflux. After 4 hours, cool to ambient temperature and concentrate invacuo to give a residue. Combine the residue and ethanol (150 mL).Evaporate in vacuo to a volume of about 75 mL and cool to give a solid.Collect solid by filtration, rinse with ethanol and then diethyl ether,and dry in vacuo to give 4-(1H-benzimidazol-2-yl)[1,4 ]diazepanehydrobromic acid salt. Elemental Analysis calculated for C₁₂H₁₆N₄•2HBr:C, 38.12; H, 4.80; N, 14.82. Found: C, 38.17; H, 4.84; N, 14.60.

Combine 4-(1H-benzimidazol-2-yl)[1,4]diazepane hydrobromic acid salt(5.2 g, 13.8 mmol), 4/l tetrahydrofuran/water (100 mL), and sodiumbicarbonate (3.47 g, 41.3 mmol). Add di-t-butyl dicarbonate (3.3 g, 15.1mmol). After 18 hours, concentrate the reaction mixture invacuo toremove most of the tetrahydrofuran and combine the concentrated reactionmixture with 5% methanol/dichloromethane. Extract with water, dry overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with ethyl acetate to give the titlecompound: mp; 225-226° C. R_(f)=0.28 (silica gel, 5%methanol/dichloromethane/0.1% concentrated aqueous ammonia).

EXAMPLE 46

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine

46.1.1 Synthesis of 3-cyano-3-(pyrid-4-yl)-pentanedioic acid diethylester

Prepare by the method of Example 34.1.2 using 4-pyridineacetonitrile togive, after chromatography on silica gel eluting with ethylacetate/hexane 1/1, the title compound.

46.2 Synthesis of (3-(pyrid-4-yl)-5-oxopyrrolidin-3-yl)acetic acid ethylester

Prepare by the method of Example 34.2.2 using3-cyano-3-(pyrid-4-yl)pentanedioic acid diethyl ester to give the titlecompound: R_(f)=0.46 (silica gel, 8% methanol/dichloromethane).

46.3 Synthesis of 3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 34.3.3 using3-(pyrid-4-yl)-5-oxo-pyrrolidin-3-yl)acetic acid ethyl ester to give thetitle compound: R_(f)=0.23 (silica gel, 15% methanol/dichloromethane).

46.4 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 7.4 using3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine to give the title compound:R_(f)=0.42 (silica gel, 8% methanol/dichloromethane).

46.5 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-hydroxyethyl)pyrrolidine(0.32 g, 0.83 mmol) and N,N-diisopropylethylamine (0.46 mL, 2.64 mmol)in dichloromethane (50 mL). Cool in an ice bath. Add dropwisemethanesulfonyl chloride (0.096 mL, 1.24 mmol). After 1 hour, warm toambient temperature. Again cool in an ice bath and addN,N-diisopropylethylamine (0.23 mL, 1.32 mmol) followed bymethanesulfonyl chloride (0.096 ml, 1.24 mmol). After 1 hour, dilute thereaction mixture with dichloromethane and extract with a saturatedaqueous solution of sodium bicarbonate. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give the title compound:R_(f)=0.24 (silica gel, 5% methanol/dichloromethane/0.1% concentratedaqueous ammonia).

46.6 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(pyrid-4-yl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.90 g, 1.65 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.49 g, 0.83mmol), and N,N-diisopropylethylamine (2.1 mL, 11.6 mmol) inacetronitrile (14 mL). Heat to reflux. After 48 hour, add sodiumcarbonate and stir. After 1 hour, dilute the reaction mixture withdichloromethane, filter and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially with 10%methanol/dichloromethane/0.1% concentrated aqueous ammonia and then 50%methanol/dichloromethane/0.1% concentrated aqueous ammonia to give aresidue. Dissolve the residue in dichloromethane, extract with asaturated aqueous sodium bicarbonate solution, dry over Na₂SO₄, filter,and evaporate in vacuo to give the title compound: R_(f)=0.39 (silicagel, 10% methanol/dichloromethane/0.1% concentrated aqueous ammonia).

46.7 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(pyrid-4-yl)pyrrolidine(0.36 g, 0.51 mmol) and dichloromethane 50 mL. Add a solution ofhydrochloric acid in dioxane (0.128 mL, 4 M, 0.51 mmol). After 2 hours,evaporate in vacuo to give a residue. Combine the residue anddichloromethane (5 mL) and add diethyl ether (200 mL) to give a solid.collect the solid by filtration, rinse with diethyl ether, and dry togive the title compound: mp; 85-95° C.

PREPARATION 11

2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride

Combine 2-hydroxy-5-nitrobenzoic acid (21.5 g, 117 mmol), potassiumcarbonate (162.3 g, 1.174 mol), and methyl iodide (136.8 g, 96.4 mmol)in acetone (500 mL). Heat to reflux. After 18 hours, cool the reactionmixture to ambient temperature and add methyl iodide (136.8 g, 96.4mmol). Again, heat to reflux. After 56 hours, cool the reaction mixtureto ambient temperature and filter, rinse with acetone, and evaporate thefiltrate in vacuo to give a residue. Recrystallize the residue formethanol to give a second residue. Combine the second residue andchloroform (about 100 mL), filter and evaporate the filtrate in vacuo togive methyl 2-methoxy-5-nitrobenzoate. R_(f)=0.38 (silica gel, ethylacetate/hexane 1/1).

Combine methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mmol) and methanol.Add 5% palladium-on-carbon (0.66 g). Hydrogenate on a pressure apparatusat 50 psi. After 17 hours, filter through celite to remove the catalystand evaporate the filtrate in vacuo to give a residue. Combine theresidue and dichloromethane and extract with water. Dry the organiclayer over Na₂SO₄, filter, and evaporate in vacuo to give methyl2-methoxy-5-aminobenzoate. R_(f)=0.18 (silica gel, ethylacetate/methanol 1/1). Elemental Analysis calculated for C₉H₁₁NO₃: C,59.66; H, 6.12; N, 7.73. Found: C, 59.44; H, 6.04; N, 7.62.

Combine methyl 2-methoxy-5-aminobenzoate (3.94 g, 21.7 mmol) andtriethyl orthoformate (12.8 g, 86.7 mmol) in glacial acetic acid (20mL). After 20 hours, concentrate the reaction mixture in vacuo to removeethanol. Add glacial acetic acid (20 mL) and sodium azide (5.64 g, 86.7mmol). Heat to 70° C. After 1 hour, add glacial acetic acid (10 mL) andcontinue to heat to 70° C. After an additional hour, cool the reactionmixture to ambient temperature, dilute with water (500 mL). Collect thesolid by filtration, rinse with water, and dry to give methyl2-methoxy-5-(1H-tetrazol-1-yl)benzoate.

Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (2.86 g, 12.2mmol) and a 1 M aqueous solution of sodium hydroxide (13.43 mL, 13.43mmol) in methanol/water (100 mL, 5:1 vol./vol.). Heat to reflux. After 4hours, concentrate in vacuo to remove most of the methanol, add water(50 mL), and adjust the pH to about 4 using a 1 M aqueous hydrochloricacid solution. Evaporate in vacuo to give a solid, slurry the solid withwater, filter, and dry to give 2-methoxy-5-(1H-tetrazol-1-yl)benzoicacid.

Alternately, combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (13.3g, 56.8 mmol) and methanol (150 mL). Add 1 M aqueous solution of sodiumhydroxide (62.5 mL, 62.5 mmol). Heat to reflux. After 30 minutes, addmethanol (50 mL) and water (50 mL) and continue the heat at reflux.After 1 hour, concentrate in vacuo to remove most of the solvent. Adjustthe pH to about 1 to 2 using a 1 M aqueous hydrochloric acid solution togive a solid. Collect the solid by filtration, rinse with water, and dryto give 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.

Combine 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid (1.2 g, 5.5 mmol) anddichloromethane (40 mL). Add dropwise oxalyl chloride (0.72 mL, 8.25mmol) followed by dimethylformamide (3 drops). After 4 hours, evaporatein vacuo and dry to give the title compound.

EXAMPLE 47

1-2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3(2-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

47.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Add (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (6.72 g, 11.0 mmol) and sodiumbicarbonate (4.87 g, 58 mmol) in acetone/water (50 mL/50 mL). Cool in anice bath. Add a solution of 2-methoxy-5-(1H-tetrazol-1-yl)benzoylchloride (1.66 g, 9.9 mmol) in acetone (100 mL). After 30 minutes, warmto ambient temperature. After 60 hours, filter the reaction mixture anddilute the filtrate with ethyl acetate. Extract the filtrate with asaturated aqueous sodium bicarbonate solution and then brine. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to giveresidue. Chromatograph the residue on silica gel eluting sequentiallywith ethyl acetate, 3% methanol/ethyl acetate, and then 5%methanol/ethyl acetate to give the title compound: R_(f)=0.48 (5%methanol/dichloromethane).

47.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(2.6 g, 6.50 mmol) and methanesulfonyl chloride (0.8 mL, 10.4 mmol) togive the title compound: R_(f)=0.20 (silica gel, ethyl acetate).

47.3 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.92 g, 1.95 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.6 g, 2.9 mmol), and N,N-diisopropylethylamine (2.2 mL, 12.6mmol) in acetonitrile (36 mL). Heat to reflux. After 22 hours, cool andpartition the residue between a saturated aqueous sodium bicarbonatesolution and ethyl acetate. Separate the organic layer and extract witha saturated aqueous sodium bicarbonate solution and then brine. Dry theorganic layer over Na₂SO₄, filter, and evaporate in vacuo to giveresidue. Chromatograph the residue on silica gel eluting withdichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1 to givethe title compound.

47.4 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(1.11 g, 1.67 mmol) and dichloromethane. (10 mL). Cool in an ice bath.Add a solution of hydrochloric acid in dioxane (1 mL, 4 M, 40. mmol).Warm to ambient temperature. Add diethyl ether (200 mL) and stir to givea solid. After 1 hour, collect the solid by filtration and dry to givethe title compound.

EXAMPLE 48

1-(3,5-Dimethoxy-4-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

48.1 Synthesis of1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7 mmol)(prepared by extraction from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL). Add3,5-dimethoxy-4-hydroxybenzoic acid (0.55 g, 2.78 mmol),1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g, 2.9mmol). After 18 hours, dilute the reaction mixture with dichloromethaneand extract with saturated aqueous sodium bicarbonate solution and thenbrine. Dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give residue. Chromatograph the residue on silica gel eluting withmethanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1 to givethe title compound: R_(f)=0.74 (silica gel,methanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1)

48.2 Synthesis of1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-phenyl-3-2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) indichloromethane (15 mL). Cool the reaction mixture to −5° C. with ansalt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol).Warm to ambient temperature. After 18 hours, quench the reaction by theaddition of ice. Separate the organic layer and extract with aqueous 1Mhydrochloric acid solution. Dry the organic layer over Na₂SO₄, filter,and concentrate in vacuo to obtain the title compound.

48.3 Synthesis of1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.77 g, 1.46 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.0 g, 1.8 mmol), and N,N-diisopropylethylamine (0.76 g, 4.4 mmol)in acetonitrile (36 mL). Heat to reflux. After 16 hours, cool andevaporate in vacuo to give residue. Chromatograph the residue on silicagel eluting with dichloromethane/methanol/concentrated aqueous ammonia6/1/0.1 to give the title compound.

48.4 Synthesis of1-(3,5-dimethoxy-4-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,5-dimethoxy-4-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.5 g, 0.5 mmol) and methanol (4 mL). Add potassium carbonate (0.5 g).After 18 hours, add a 1 M aqueous sodium hydroxide solution (1 mL) andextract with dichloromethane. Dry the organic layer over Na₂SO₄, filter,and concentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with dichloromethane/methanol/concentrated aqueousammonia 6/1/0.1 to give a residue. Combine the residue anddichloromethane (4 mL). Add a solution of hydrochloric acid in dioxane(0.12 mL, 4 M, 0.48 mmol). Warm to ambient temperature. After 1 hour,evaporate in vacuo to give a residue. Triturate with diethyl ether togive a solid. After 1 hour, collect the solid by filtration and dry togive the title compound.

EXAMPLE 49

1-(3,4-Dimethoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

49.1 Synthesis of1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.50 g, 2.7 mmol)(prepared by extraction from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and dichloromethane (25 mL). Add3,4-dimethoxy-5-hydroxybenzoic acid (0.55 g, 2.78 mmol),1-hydroxybenzotriazole hydrate (0.4 g, 2.9 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.56 g, 2.9mmol). After 18 hours, dilute the reaction mixture with dichloromethaneand extract with saturated aqueous sodium bicarbonate solution and thenbrine. Dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give residue. Chromatograph the residue on silica gel eluting withmethanol/dichloromethane/concentrated aqueous ammonia 1/10/0.1 to givethe title compound.

49.2 Synthesis of1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) indichloromethane (15 mL). Cool the reaction mixture to −5° C. with ansalt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol).Warm to ambient temperature. After 18 hours, quench the reaction by theaddition of ice. Separate the organic layer and extract with aqueous 1Mhydrochloric acid solution. Dry the organic layer over Na₂SO₄, filter,and concentrate in vacuo to obtain the title compound.

49.3 Synthesis of1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.77 g, 1.46 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.0 g, 1.8 mmol), and N,N-diisopropylethylamine (0.76 g, 4.4 mmol)in acetonitrile (36 mL). Heat to reflux. After 16 hours, cool andevaporate in vacuo to give residue. Chromatograph the residue on silicagel eluting with dichloromethane/methanol/concentrated aqueous ammonia6/1/0.1 to give the title compound.

49.4 Synthesis of1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4-dimethoxy-5-methanesulfonyloxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.5 g, 0.5 mmol) and methanol (4 mL). Add potassium carbonate (0.5 g).After 18 hours, add a 1 M aqueous sodium hydroxide solution (1 mL) andextract with dichloromethane. Dry the organic layer over Na₂SO₄, filter,and concentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with dichloromethane/methanol/concentrated aqueousammonia 6/1/0.1 to give a residue. Combine the residue anddichloromethane (4 mL). Add a solution of hydrochloric acid in dioxane(0.12 mL, 4 M, 0.48 mmol). Warm to ambient temperature. After 1 hour,evaporate in vacuo to give a residue. Triturate with diethyl ether togive a solid. After 1 hour, collect the solid by filtration and dry togive the title compound.

EXAMPLE 50

1-(2-(4-Carboxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

50.1 Synthesis of1-(2-hydroxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (2.0 g, 5.1 mmol) and anhydrousdichloromethane (100 mL). Cool in an ice bath. Add a solution of borontribromide (17.8 mL, 1 M, 17.8 mmol) and stir. After 2 hours, pour thereaction mixture into ice-water and stir vigorously. After 18 hours,separate the layers and extract the organic layer with water. Saturatethe aqueous layer with sodium chloride and extract with dichloromethane.Combine the organic layers, dry over Na₂SO₄, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia togive a residue. combine the residue and toluene/methanol. Evaporate invacuo to give a residue, dissolve in dichloromethane, filter, evaporate,combine with dichloromethane, again evaporate to remove residual tolueneto give the title compound: mp; 86-96° C., R_(f)=0.37 (silica gel, 5%methanol/dichloromethane/0.5% concentrated aqueous ammonia).

50.2 Synthesis of1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine1-(2-hydroxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(0.19 g, 0.5 mmol) and dimethylformamide (5 mL). Add potassium carbonate(82 mg, 0.6 mmol) and 1-bromo-3-carboethoxypropane (0.21 mL, 0.29 g, 1.5mmol). Heat at 100° C. After 2.5 hours, cool to ambient temperature.After 18 hours, dilute the reaction mixture with ethyl acetate, extractwith water, aqueous 1 M hydrochloric acid solution, and then brine. Drythe organic layer over Na₂SO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 5%methanol/dichloromethane/0.5% concentrated aqueous ammonia to give thetitle compound: R_(f)=0.28 (silica gel, 5% methanol/dichloromethane/0.5%concentrated aqueous ammonia).

50.3 Synthesis of1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Combine1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(0.15 g, 0.3 mmol) and dichloromethane (5 mL). Cool in an ice bath. AddN,N,-diisopropylethylamine (0.12 mL, 86.5 mg, 0.67 mmol), andmethanesulfonyl chloride (0.035 mL, 52 mg, 0.46 mmol). After 2 hours,dilute the reaction mixture with dichloromethane and extract withaqueous 1 M hydrochloric acid solution, water, and then a saturatedaqueous solution of sodium bicarbonate. Dry the organic layer overNa₂SO₄, filter, and evaporate in vacuo to give the title compound:R_(f)=0.23 (silica gel, ethyl acetate).

50.4 Synthesis of1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(2-(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.17 g, 0.3 mmol), N,N,-diisopropylethylamine (0.24 mL, 175 mg, 1.35mmol), and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt (0.33 g, 0.6 mmol) in acetonitrile (5 mL). Heat toreflux. After 22 hours, cool the reaction mixture, dilute with ethylacetate, extract with a saturated aqueous solution of sodium bicarbonateand then brine. Dry the organic layer over Na₂SO₄, filter, and evaporatein vacuo to give a residue. Chromatograph the residue on silica geleluting sequentially with 10% methanol/dichloromethane/0.5% concentratedaqueous ammonia and then methanol to give, after drying,the titlecompound: R_(f)=0.10 (silica gel, 5% methanol/dichloromethane/0.5%concentrated aqueous ammonia/ethyl acetate).

50.5 Synthesis of1-(2-(3-carboxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinelithium salt

Combine1-(2-1(3-carboethoxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.185 g, 0.24 mmol) and lithium hydroxide hydrate (23 mg, 0.97 mmol) intetrahydrofuran/water 3/1 (5 mL). After 2 hours, evaporate in vacuo togive a residue. Triturate the residue with dichloromethane. Evaporatethe dichloromethane to give, after drying, the title compound.

50.6 Synthesis of1-(2-(3-carboxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-(3-carboxypropyloxy)-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinelithium salt (0.18 g, 0.24 mmol) and dichloromethane (5 mL). Add asolution of hydrochloric acid in dioxane (0.18 mL, 4 M, 0.72 mmol). Addmethanol (5 mL) and evaporate in vacuo to give a residue. Dissolve theresidue in methanol (about 5 mL) and add 10% methanol/diethyl ether (90mL) to form a solid. Decant the solvent and add diethyl ether (90 mL)and stir. After 30 minutes collect the solid by filtration and dry invacuo at 110° C., to give the title compound: mp; 155-175° C.

PREPARATION 12.1

3-(2-(4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared by extractionfrom (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (20 g, 32.8 mmol) and sodiumbicarbonate (16.5 g, 197 mmol) in acetone/water (160 mL/80 mL). Adddropwise benzyl chloroformate (4.7 mL, 32.8 mmol). After 16 hours,evaporate the reaction mixture in vacuo to give a residue. Combine theresidue and dichloromethane, extract with water and then brine, to givea residue. Dry the organic layer over MgSO₄, filter, and evaporate invacuo to give residue. Chromatograph the residue on silica gel elutingwith methanol/dichloromethane 1/7 containing 1% concentrated aqueousammonia to give 1-carbobenzyloxy-3-phenyl-3-(2-hydroxyethyl)pyrrolidine.

Combine 1-carbobenzyloxy-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (9.6 g,29.6 mmol) and triethylamine (8.2 mL, 59.2 mmol) in dichloromethane (150mL). Cool in an ice-bath. Add methanesulfonyl chloride (2.5 mL, 32.6mmol). After 16 hours, dilute the reaction mixture with dichloromethaneand extract with brine. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give residue. Chromatograph the residue on silicagel eluting with methanol/dichloromethane 1/10 containing 1%concentrated aqueous ammonia to give1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine.

Combine1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (10.2g, 25.3 mmol), (1.34 g, 2.5 mmol),4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (16.5 g, 30.4 mmol), and N,N-diisopropylethylamine (18 mL, 101mmol) in acetonitrile (300 mL). Heat to reflux. After 18 hours,evaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 1/6 containing 1% concentrated aqueous ammoniato give1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine.

Alternately, combine1-carbobenzyloxy-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (5.7g, 14.1 mmol), 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt (7.52 g, 213.8 mmol), and N,N-diisopropylethylamine(9.6 mL, 55 mmol) in acetonitrile (200 mL). Heat to reflux. After 18hours, evaporate in vacuo to give a residue. Combine the residue anddichloromethane. Extract twice with saturated aqueous sodium bicarbonatesolution and then brine. Dry the organic layer over Na₂SO₄, filter, andevaporate in vacuo to give residue. Chromatograph the residue on silicagel eluting sequentially with ethyl acetate and then 5%methanol/dichloromethane to give1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine: R_(f)=0.38 (silica gel,5% methanol/dichloromethane).

Combine1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine3.78 g, 6.35 mmol) and potassium hydroxide (1.07 g, 19.0 mmol) inisopropanol (150 mL). Heat to reflux. After 66 hours, cool the reactionmixture and evaporate in vacuo to give a residue. dilute the residuewith dichloromethane (300 mL) and extract with brine. Dry the organiclayer over Na₂SO₄, filter, and evaporate in vacuo to give residue.Chromatograph the residue on silica gel eluting sequentially with 10%methanol/dichloromethane/0.1% concentrated aqueous ammonia/methanol, andthen 5% concentrated aqueous ammonia/methanol to give a residue. Combinethe residue and dichloromethane, filter, extract with a saturatedaqueous sodium bicarbonate solution, dry over Na₂SO₄, filter, andevaporate in vacuo to give3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine.

Alternately, combine1-carbobenzyloxy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(1.23 g, 2.06 mmol) in ethanol (20 mL). Add 10% palladium-on-carbon (0.2g) and palladium hydroxide (0.2 g). Hydrogenate on a pressure apparatusat 50 psi. After 72 hours, remove the catalyst by filtration, andevaporate in vacuo to give a residue. Combine the residue anddichloromethane (50 mL). Add a solution of hydrochloric acid an dioxane(1.01 mL, 4 M, 4.0 mmol) and stir. After 3 hours, add dither ether (180mL) to give a solid. Collect the solid by filtration and dry to give3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt: mp; 117-126° C.

PREPARATION 12.2

3-(2-(4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (11.1 g, 18.3 mmol) andacetone/water (1/1, 200 mL). Cool to about 0° C. in an ice bath and addsodium bicarbonate (10.6 g, 217.6 mmol). Warm to ambient temperature andslowly add a solution of benzoyl chloride (4.2 g, 365 mmol) in acetone(10 mL). After 18 hours, filter and dilute the filtrate with ethylacetate. Extract the diluted filtrate with a saturated aqueous sodiumbicarbonate solution and then brine. Dry the organic layer over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with dichloromethane/methanol 95/5 to give1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine: R_(f)=0.81 (silicagel, dichloromethane/methanol 95/5).

Prepare 1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine bythe method of Example 2.5.2 using1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine.

Prepare1-benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineby the method of Example 8.4 using1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine.

Combine 1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(7.22 g, 12.76 mmol) and ethylene glycol (200 mL). Add potassiumhydroxide (5.13 g, 91.4 mmoL) and hydrazine hydrate (4.4 mL, 90.7 mmol).Heat to reflux. After 18 hours, dilute the reaction mixture with waterand extract three times with dichloromethane. Combine the organic layersand extract with brine. Dry over MgSO₄, filter, and evaporate in vacuoto give a residue. Chromatograph the residue on silica gel elutingsequentially with methanol/dichloromethane/concentrated aqueous ammonia50/50/0.5, methanol/dichloromethane/concentrated aqueous ammonia75/25/0.75 and then methanol/concentrated aqueous ammonia 100/1.0.Combine the product containing fractions, evaporate in vacuo, combinewith dichloromethane, and extract twice with water, dry over MgSO₄,filter, and evaporate in vacuo to give the title compound: R_(f)=0.38(silica gel, methanol/dichloromethane/concentrated aqueous ammonia10/90/0.1).

PREPARATION 12.3

3-(2-(4-(1-(2-Ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine 3-phenyl-3-(2-hydroxyethyl)pyrrolidine (prepared by extractionfrom (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (20 g, 32.8 mmol) and sodiumhydroxide (2.8 g, 70 mmol) in tetrahydrofuran/water (120 mL/120 mL). Adddropwise a solution of di-t-butyl dicarbonate (32.8 mmol) intetrahydrofuran (60 mL). After 16 hours, evaporate the reaction mixturein vacuo to give a residue. Combine the residue and dichloromethane,extract with aqueous 1 M sodium hydroxide solution, water, and thenbrine. Dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give 1-t-butoxycarbonyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine. [α]²_(D) ⁰=+55.4° (c=0.932, chloroform).

Prepare1-t-butoxycarbonyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine bythe method of Preparation 12.1 using1-t-butoxycarbonyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine.

Prepare1-t—butoxycarbonyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineby the method of Preparation 12.1 using1-t-butoxycarbonyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt to give1-t-butoxycarbonyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine.[α]² _(D) ⁰=+14.2° (c=1.07, chloroform).

Combine1-t-butoxycarbonyl-3-(2-(4-(1-(2ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(5.0 g) and dichloromethane (50 mL). Add a solution of hydrochloric acidin dioxane (10 mL, 4 M, 40 mmol). After 8 hours, evaporate in vacuo togive3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt.

PREPARATION 13

2-Methylthio-5-(1H-tetrazol-1-yl)benzoic acid

Combine 2-fluoro-5-nitrobenzoic acid (prepared by the method ofTetrahedron, 23, 4041-4045 (1967)) (3.7 g, 20 mmol) and sodiumthiomethoxide (2.8 g, 40 mmol) in methanol (60 mL). Heat to reflux.After 24 hours, cool the reaction mixture, adjust the pH to about 2using aqueous 1 M hydrochloric acid solution. Extract the reactionmixture with ethyl acetate. Dry the organic layer over MgSO₄, filter,and evaporate in vacuo to give 2-methylthio-5-nitrobenzoic acid:R_(f)=0.5 (silica gel, 10% methanol/dichloromethane).

Combine 2-methylthio-5-nitrobenzoic acid, (3.2 g, 15 mmol),N,N-diisopropylethylamine (17.0 mL, 100 mmol), and methyl iodide (12.45mL, 200 mmol) in acetonitrile (50 mL). After 18 hours, dilute thereaction mixture with ethyl acetate, extract with brine, dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 20% ethylacetate/hexane to give methyl 2-methylthio-5-nitrobenzoate. R_(f)==0.58(silica gel, 30% ethyl acetate/hexane).

Combine methyl 2-methylthio-5-nitrobenzoate (2.9 g, 12.7 mmol) andglacial acetic acid (100 mL). Heat to 90° C. Add iron powder (5 g) andwater (20 mL) over about 10 minutes. After 30 minutes, the reactionmixture was filtered while still hot and diluted with water (500 mL).Extract the reaction mixture with ethyl acetate. Dry the organic layerover MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 20% ethylacetate/hexane to give methyl 2-methylthio-5-aminobenzoate. R_(f)=0.51(silica gel, 30% ethyl acetate/hexane).

Combine methyl 2-methylthio-5-aminobenzoate (2.18 g, 11.1 mmol) andtriethyl orthoformate (7.4 mL, 44.3 mmol) in glacial acetic acid (20mL). After the formation of a yellow solid, add glacial acetic acid (40mL). After 50 minutes, add sodium azide (2.9 g, 44.3 mmol). Heat to 70°C. After 2 hours, cool the reaction mixture to ambient temperature andstir. After 56 hours, cool in an ice bath and dilute with water (400 mL)to give a solid. After 1 hour, collect the solid by filtration, rinsewith water, and dry to give methyl2-methylthio-5-(1H-tetrazol-1-yl)benzoate: R_(f)=0.90 (silica gel, 10%methanol/ethyl acetate).

Combine methyl 2-methylthio-5-(1H-tetrazol-1-yl)benzoate (0.5 g, 2.0mmol) and a 1 M aqueous solution of sodium hydroxide (20 mL, 20 mmol) inmethanol (20 mL). After 2 hours, adjust the pH to about 2 using a 1 Maqueous hydrochloric acid solution and extract with ethyl acetate. Drythe organic layer over MgSO₄, filter, and concentrate in vacuo to givethe title compound: R_(f)=0.70 (silica gel, 10% methanol/85%chloroform/5% acetic acid).

EXAMPLE 51

1-(2-Methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

51.1 Synthesis of1-(2-methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) (0.53 g, 1.0 mmol) and dichloromethane (10 mL). Add2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.24 g, 1.0 mmol),1-hydroxybenzotriazole hydrate (0.16 f, 1.2 mmol),N,N-diisopropylethylamine (0.34 mL, 2.0 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2mmol). After 18 hours, dilute the reaction mixture with ethyl acetateand extract with brine. Dry the organic layer over Na₂SO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting sequentially with ethyl acetate, 2% methanol/ethylacetate, and the 8% methanol/ethyl acetate to give a residue. Combinethe residue and dichloromethane, extract with brine, twice with asaturated aqueous solution of ammonium chloride, and then a saturatedaqueous solution of sodium bicarbonate. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give the title compound:R_(f)=0.34 (silica gel, 10% methanol/ethyl acetate).

51.2 Synthesis of1-(2-methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methylthio-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.35 g, 0.52 mmol) and dichloromethane (20 mL). Add a solution ofhydrochloric acid in dioxane (0.26 mL, 4 M, 1.04 mmol). After 1 hour,evaporate in vacuo to give a residue. Combine the residue and diethylether (50 mL) and stir to give a solid. After 18 hours, collect thesolid by filtration to give, after drying, the title compound.

PREPARATION 14

2-Methylsulfonyl-5-(1H-tetrazol-1-yl)benzoic acid

Combine 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.68 g, 0.29mmol), 30% hydrogen peroxide (3 ml.) and glacial acetic acid (20 mL).After 2 hours, heat to 100° C. After 2 hours, cool to ambienttemperature and add water (250 mL) to give a solid. Collect the solid byfiltration and dry to give the title compound: R_(f)=0.21 (silica gel,10% methanol/85% dichloromethane/5% acetic acid).

EXAMPLE 52

1-(2-Methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

52.1 Synthesis of1-(2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) (0.53 g, 1.0 mmol) and dichloromethane (10 mL). Add2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoic acid (0.27 g, 1.0 mmol),1-hydroxybenzotriazole hydrate (0.16 g, 1.2 mmol),N,N-diisopropylethylamine (0.34 mL, 2.0 mmol), and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.23 g, 1.2mmol). After 18 hours, dilute the reaction mixture with ethyl acetateand extract with brine. Dry the organic layer over Na₂SO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting sequentially with 2% methanol/ethyl acetate and then5% methanol/ethyl acetate give the title compound: R_(f)=0.41 (silicagel, 10% methanol/ethyl acetate)

52.2 Synthesis of1-(2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methylsulfonyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.59 g, 0.83 mmol) and dichloromethane (20 mL). Add a solution ofhydrochloric acid in dioxane (0.415 mL, 4 M, 1.66 mmol) and stir. After1 hour, evaporate in vacuo to give a residue. Triturate the residue withdiethyl ether and stir to give a solid. After 18 hours, collect thesolid by filtration and dry to give the title compound.

PREPARATION 17

2-Methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoic acid

Combine methyl 2-methoxy-5-aminobenzoate (1.8 g, 10 mmol) and pyridine(0.88 mL, 11 mmol) in tetrahydrofuran (10 mL). Cool in an ice bath. Addtrifluoroacetic anhydride (1.56 mL, 11 mmol). Warm to ambienttemperature. After 2 hours, add water and dilute the reaction mixturewith ethyl acetate. Separate the organic layer, extract with brine, dryover MgSO₄, filter, and evaporate in vacuo to give methyl2-methoxy-5-trifluoroacetylamidobenzoate.

Combine methyl 2-methoxy-5-trifluoroacetylamidobenzoate (3.1 g, 15mmol), triphenylphosphine (5.2 g, 20 mmol) and carbon tetrachloride (30mL) in tetrahydrofuran (30 mL). Heat to reflux. After 18 hours, addcarbon tetrachloride (100 mL) and continue to heat at reflux. After 18hours, evaporate in vacuo to give a residue. Chromatograph the residueon a short column of silica gel eluting with 30% ethyl acetate/hexane togive methyl 2-methoxy-5-(2-trifluoromethyl-2-chloroiminobenzoate.

Combine methyl 2-methoxy-5-(2-trifluoromethyl-N2chloroiminobenzoate (3.4g, 12 mmol) and sodium azide (3.12 g, 48 mmol) in glacial acetic acid(60 mL). Heat to 70° C. After 3 hours, cool the reaction mixture in anice bath, add water (800 mL), and stir to give a solid. After 1 hour,collect the solid by filtration and dry to give methyl2-methoxy-5-(5-trifluormethyl-1H-tetrazol-1-yl)benzoate: R_(f)=0.58(silica gel, 30% ethyl acetate/toluene).

Combine methyl 2-methoxy-5-(5-trifluormethyl-1H-tetrazol-1-yl)benzoate(1.46 g, 5.27 mmol) and an aqueous solution of sodium hydroxide (20 mL,2 M, 40 mmol) in methanol/tetrahydrofuran (20 mL/10 mL). After 2 hours,adjust the pH of the reaction mixture to about 2 using a 1 M aqueoushydrochloric acid solution. Extract the reaction mixture with ethylacetate and then dichloromethane. Dry the combined organic layers overMgSO₄, filter, and evaporate invacuo to give a the title compound:R_(f)=0.55 (silica gel, 85% chloroform/10% methanol/5% acetic acid)

EXAMPLE 54

1(2-Methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

54.1 Synthesis of1-(2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 51.1 using3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) and 2-methoxy-5-(5-trifluoromethyl-1H-tetrazol-1-yl)benzoicacid to give the title compound.

PREPARATION 18

2-Methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoic acid

Combine methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (0.12 g, 0.5 mmol)and Eschenmoser's salt (N,N-dimethylmethyleneammonium iodide) (0.28 g,1.5 mmol) in acetic acid (5 mL). Heat to reflux. After 8 hours,evaporate invacuo to give methyl2-methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoate:R_(f)=0.30 (silica gel, ethyl acetate)

EXAMPLE 55

1-(2-Methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

55.1 Synthesis of1-(2-methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 51.1 using2-methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol-1-yl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

55.2 Synthesis of1-(2-methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(5-N,N-dimethylaminomethyl-1H-tetrazol)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound:R_(f)=0.40 (silica gel, 10%methanol/dichloromethane).

PREPARATION 19

2-Methylsulfinyl-5-(1H-tetrazol-1-yl)benzoic acid

Combine 2-methylthio-5-(1H-tetrazol-1-yl)benzoic acid (0.50 g, 2.0mmol), pyridine (20 mL) and water (20 mL). Cool in an ice bath. Addphenyltrimethylammonium tribromide (0.75 g, 2 mmol) and tetrahydrofuran(20 mL). Warm to ambient temperature. After 1 hour, add a solution a ofsodium bisulfite (1 g) in water (1 mL). Extract the reaction mixturewith ethyl acetate and then dichloromethane. Combine the organic layers,dry over MgSO₄, filter, and evaporate in vacuo to give a residue. thetitle compound. Chromatograph the residue on silica gel elutingsequentially with ethyl acetate and then 10% methanol/ethyl acetate togive methyl 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoate.

Combine methyl 2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoate (0.46 g,1.73 mmol) and a 1 M aqueous solution of sodium hydroxide (30 mL, 30mmol) in methanol (10 mL) and tetrahydrofuran (10 mL). After 1 hour,adjust the pH to about 2 using a 1 M aqueous hydrochloric acid solutionand extract with ethyl acetate and then dichloromethane. Dry thecombined organic layers over MgSO₄, filter, and concentrate in vacuo togive the title compound: R_(f)=0.15 (silica gel, 10% methanol/85%dichloromethane/5% acetic acid).

EXAMPLE 56

1-(2-Methylsulfinyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

56.1 Synthesis of1-(2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) (0.46 g, 1.0 mmol) and dichloromethane (20 mL). Add2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoic acid (0.32 g, 1.3 mmol),1-hydroxybenzotriazole hydrate (0.2 g, 1.5 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5mmol), and N,N-diisopropylethylamine (0.34 mL, 2 mmol). After 18 hours,dilute the reaction mixture with ethyl acetate and extract with brine,dry the organic layer over MgSO₄, filter, and concentrate invacuo togive a residue. Chromatograph the residue on silica gel elutingsequentially with ethyl acetate and then 10% methanol/ethyl acetate givethe title compound.

56.2 Synthesis of1-(2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methylsulfinyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.34 g, 0.49 mmol) to give the title compound.

PREPARATION 20

2-chloro-3,4,5-trimethoxybenzoic acid

Combine methyl 2-amino-3,4,5-trimethoxybenzoate (4.8 g, 20 mmol) anddichloromethane (20 mL). Cool in an ice bath. Add a solution ofhydrochloric acid in dioxane (10 mL, 4 M, 40 mmol). Add polyethyleneglycol 200 (20 mL) followed by sodium nitrite (2.76 g, 40 mmol). After10 minutes add copper (I) chloride (3.96 g, 40 mmol). Warm to ambienttemperature. After 18 hours, dilute the reaction mixture with ethylacetate and extract with a 1 M aqueous solution of sodium hydroxide anthen brine. Dry the organic layer over MgSO₄, filter, and evaporate invacuo to give a residue. the title compound. Chromatograph the residueon silica gel eluting sequentially with hexane and then 5% ethylacetate/hexane to give methyl 2-chloro-3,4,5-trimethoxybenzoate:R_(f)=0.7 (silica gel, 20% ethyl acetate/toluene).

Combine methyl 2-chloro-3,4,5-trimethoxybenzoate (2.0 g, 7.8 mmol) and a1 M aqueous solution of sodium hydroxide (100 mL, 100 mmol) in methanol(50 mL). After 6 hours, adjust the pH to about 2 using a 1 M aqueoushydrochloric acid solution and extract with dichloromethane. Dry thecombined organic layers over MgSO₄, filter, and concentrate in vacuo togive the title compound: R_(f)=0.81 (silica gel, 10% methanol/85%c.hloroform/5% acetic acid).

EXAMPLE 57

1-(2-chloro-3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

57.1 Synthesis of1-(2-chloro-3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-chloro-3,4,5-trimethoxybenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 21

2-Methoxy-5-methylthiobenzoic acid

According to the method of J. Organometallic Chem., 132, 321 (1977),combine 4-methoxythioanisole (6.3 mL, 45.3 mmol) and tetrahydrofuran (90mL). Cool in an ice bath. Add dropwise a solution of n-butyllithium (20mL, 2.5 M, 50 mmol). After 2.5 hours, pour the reaction mixture ontofreshly crushed dry-ice. Add diethyl ether and allow the dry-ice todissipate. Dilute the reaction mixture with diethyl ether and water and0.5 M aqueous sodium hydroxide solution (50 mL). Separate the layers andextract the aqueous layer with diethyl ether. Acidify the aqueous layerwith a 12 M aqueous hydrochloric acid solution (about 9.0 mL). Extractthe acidified aqueous layer three times with ethyl acetate. Combine theethyl acetate extracts, extract with brine, dry over Na₂SO₄, filter, andevaporate in vacuo to give the title compound.

EXAMPLE 58

1-(2-Methoxy-5-methylthiobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

58.1 Synthesis of1-(2-methoxy-5-methylthiobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-methylthiobenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 22

2-Methoxy-5-methylsulfinylbenzoic acid

Combine 2-methoxy-5-methylthiobenzoic acid (6.82 g, 34.4 mmol) andmethanol (65 mL). Cool in an ice bath. Add slowly dropwise thionylchloride (2.8 mL, 38 mmol). Warm to ambient temperature. After 18 hours,evaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 25% hexane/dichloromethane to give methyl2-methoxy-5-methylthiobenzoate: R_(f)=0.06 (silica gel, 65%hexane/dichloromethane).

Alternately, combine methyl 2-methoxy-5-aminobenzoate (1.0 g, 5.6 mmol)and 12 M aqueous hydrochloric acid solution (1.2 g and cool in an icebath. Add a solution of sodium nitrite (0.37 g, 5.3 mmol) in water (3mL). After 1.5 hours, add ethyl xanthic acid, sodium salt (0.76 g, 6.3mmol) and sodium carbonate (0.67 g, 6.3 mmol). After 2 hours, evaporatein vacuo and add sodium sulfide (0.69 g, 2.7 mmol) and a 1 M aqueoussodium hydroxide solution (10 mL). After 4 hours, add dimethylsulfateand heat to reflux. After 24 hours, cool to ambient temperature, acidifywith 12 M hydrochloric acid solution and extract with ethyl acetate.Separate the organic layer, extract with brine, dry over Na₂SO₄, filter,and evaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with ethyl acetate/hexane 2/1 to give methyl2-methoxy-5-methylthiobenzoate. Elemental Analysis calculated forC₉H₁₂O₃S: C, 54.53; H, 5.08. Found: C, 54.64; H, 4.95.

Combine methyl 2-methoxy-5-methylthiobenzoate (3.0 g, 14.1 mmol),pyridine (10 mL) and water (10 mL). Cool in an ice bath. Add portionwisephenyltrimethylammonium tribromide (5.84 g, 15.5 mmol). After 30minutes, warm to ambient temperature. After 3 hour, add a solution ofsodium bisulfite (1.6 g) in water (4 mL). After 10 minutes, add a 12 Maqueous hydrochloric acid solution (11 mL) and water. Extract thereaction mixture four times with dichloromethane. Combine the organiclayers, extract with brine, dry over Na₂SO₄, filter, and evaporate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith ethyl acetate to give methyl 2-methoxy-5-methylsulfinylbenzoate:mp; 64-66° C. Elemental Analysis calculated for C₉H₁₂O₄S: C, 52.62; H,5.30. Found: C, 52.51; H, 5.:37.

Combine methyl 2-methoxy-5-methylsulfinylbenzoate (2.37 g, 12.0 mmol)and a 1 M aqueous solution of potassium hydroxide (13 mL, 13 mmol). Heatto reflux. After 2 hours, cool to ambient temperature and adjust the pHto about 2 using a 1 M aqueous hydrochloric acid (14.5 mL, 14.5 mmol).Evaporate in vacuo to give a solid. Combine the solid anddichloromethane and stir. Decant the solvent and add moredicliloromethane. Again decant and combine with the first decantate, dryover Na₂SO₄, filter, and evaporate in vacuo to to give the titlecompound: mp; 114-116° C.

EXAMPLE 59

1-(2-Methoxy-5-methylsulfinylbenzoyl)-3-(2-(4-(1-2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

59.1 Synthesis of1-(2-methoxy-5-methylsulfinylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)([1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine.

Prepare by the method of Example 56.1 using2-methoxy-5-methylsulfinylbenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give, after chromatography on silica gel eluting with 10%methanol/dichloromethane, the title compound.

59.2 Synthesis of1-(2-methoxy-5-methylsulfinylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-methylsulfinylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.57 g, 0.87 mmol) and methanol (13 mL). Add a solution of hydrochloricacid in dioxane (0.44 mL, 4 M, 1.76 mmol). After 18 hours, evaporate invacuo to give a residue. Add methanol (2 mL) and then with vigorousstirring add diethyl ether to give a solid. Repeatedly, decant, adddiethyl ether, and stir. Collect the solid and dry to give the titlecompound.

PREPARATION 23

2-Methoxy-5-methylsulfonylbenzoic acid

Combine methyl 2-methoxy-5-methylthiobenzoate (1.30 g, 6.1 mmol) anddichloromethane (50 mL). Cool in an ice bath. Add m-chloroperbenzoicacid (5.28 g, 50%, 1.53 mmol). After 10 minutes, warm to ambienttemperature. After 18 hour, dilute the reaction mixture withdichloromethane. Extract with a saturated aqueous solution of sodiumbicarbonate and then brine. Dry the combined organic layers over MgSO₄,filter, and concentrate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 5% ethyl acetate/dichloromethane togive a residue. Combine the residue and dichloromethane, extract with asaturated aqueous solution of sodium bicarbonate and then brine, dryover MgSO₄, filter, and concentrate in vacuo to give a residue.Crystallize the residue from ethyl acetate/hexane to give methyl2-methoxy-5-methylsulfonylbenzoate: mp; 113-115° C.

Combine methyl 2-methoxy-5-methylsulfonylbenzoate (2.24 g, 9.2 mmol) anda 1 M aqueous potassium hydroxide solution (10 mL, 10 mmol). Heat toreflux. After 2 hours, filter while still hot, cool in an ice bath, andacidify by dropwise addition of a 1 M aqueous hydrochloric acid solution(11 mL) to give a solid. Collect the solid by filtration, rinse withwater, and dry to give the title compound: mp; 189-191° C. ElementalAnalysis Calculated for C₉H₁₀SO₅: C, 46.95; H, 4.38. Found: C, 46.76; H,4.40.

EXAMPLE 60

1-(2-Methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

60.1 Synthesis of1-(2-methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-methylsulfonylbenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound: R_(f)=0.31L (silica gel, 5%methanol/dichloromethane).

60.2 Synthesis of1-(2-methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-methylsulfonylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.45 g, 0.66 mmol) and methanol (10 mL). Add a solution of hydrochloricacid in dioxane (0.34 mL, 4 M, 1.36 mmol). After 18 hours, evaporate invacuo to give a residue. Add methanol (2 mL) and then with vigorousstirring add diethyl ether to give a solid. Decant, collect the solid,and dry to give the title compound.

PREPAPATION 24

3-Methoxy-4,5-methylenedioxybenzoic acid

Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.93 g, 4.6 mmol) andpotassium carbonate (3.2 g, 23.4 mmol) in acetone (25 mL) anddimethylformamide (25 mL). Add diiodomethane (6.3 g, 23.3 mmol). Heat toreflux. After 24 hours, cool in an ice bath, acidify with a 1 M aqueoushydrochloric acid solution (35 mL), and extract twice with ethylacetate. Combine the organic layers and extract with brine. Dry overMgSO₄, filter, and concentrate in vacuo to give methyl3-methoxy-4,5-methylenedioxybenzoate.

Combine methyl 3-methoxy-4,5-methylenedioxybenzoate (0.84 g, 4.0 mmol)and tetrahydrofuran (25 mL). Add a 1 M aqueous solution of lithiumhydroxide (8.0 mL, 8.0 mmol). Heat to reflux. After 4 hours, cool thereaction, concentrate in vacuo to remove most of the tetrahydrofuran.Extract with ethyl acetate. Cool in a ice bath and acidify the aqueouslayer with a 6 M aqueous hydrochloric acid solution to give a solid.collect the solid by filtration and dry to give the title compound.

EXAMPLE 61

1-(3-Methoxy-4,5-methylenedioxybenzoyl-3(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

61.1 Synthesis of1-(3-methoxy-4,5-methylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using3-methoxy-4,5-methylenedioxybenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 25

3-Methoxy-4,5-ethylenedioxybenzoic acid

Combine methyl 3-methoxy-4,5-dihydroxybenzoate (0.5 g, 2.5 mmol) andpotassium carbonate (1.74 g, 12.65 mmol) in acetone (25 mL). Adddibromoethane (2.37 g, 12.65 mmol). Heat to reflux. After 24 hours, coolin an ice bath, acidify with a 1 M aqueous hydrochloric acid solution(35 mL), add water (25 mL), and extract three times with ethyl acetate.Combine the organic layers and extract with brine. Dry over MgSO₄,filter, and concentrate in vacuo to give methyl3-methoxy-4,5-ethylenedioxybenzoate.

Combine methyl 3-methoxy-4,5-ethylenedioxybenzoate (0.46 g, 2.0 mmol)and tetrahydrofuran (15 mL). Add a 1 M aqueous solution of lithiumhydroxide (2.5 mL, 2.5 mmol). Heat to reflux. After 15 hours, cool thereaction, concentrate in vacuo to remove most of the tetrahydrofuran.Cool in a ice bath and acidify with a 1 M aqueous hydrochloric acidsolution to give a solid. Collect the solid by filtration and dry togive the title compound.

EXAMPLE 62

1-(3-Methoxy-4,5-ethylenedioxybenzoyl)-3-(2-(4-(1(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

62.1 Synthesis of1-(3-methoxy-4,5-ethylenedioxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using3-methoxy-4,5-ethylenedioxybenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

EXAMPLE 63

1-Benzoyl-3-2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

63.1.1 Synthesis of 1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (11.1 g, 18.3 mmol) andacetone/water (1/1, 200 mL). Cool to about 0° C. in an ice bath and acidsodium bicarbonate (10.6 g, 217.6 mmol). Warm to ambient temperature andslowly add a solution of benzoyl chloride (4.2 g, 365 mmol) in acetone(10 mL). After 18 hours, filter and dilute the filtrate with ethylacetate. Extract the diluted filtrate with a saturated aqueous sodiumbicarbonate solution and then brine. Dry the organic layer over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with dichloromethane/methanol 95/5 to givethe title compound: R_(f)=0.81 (silica gel, dichloromethane/methanol95/5).

63.1.2 Synthesis of 1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (40 g, 65.6 mmol) and sodiumbicarbonate (33 g, 394 mmol) in tetrahydrofuran/water (200 mL/200 mL).With vigorous stirring, add benzoyl chloride (8.4 g, 72.7 mmol). After 3hours, partition between ethyl acetate and water. Separate the layersand extract the aqueous layer with ethyl acetate. Combine the organiclayers and extract with water and then brine. Dry the organic layer overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting sequentially with dichloromethane andthen dichloromethane/methanol 95/5 to give the title compound.

63.2 Synthesis of 1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-benzoyl-3-phenyl-3-(2-hydroxyethyl)pyrrolidine to give the titlecompound: R_(f)=0.34 (silica gel, ethyl acetate).

63.3 Synthesis of1-benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 8.4 using1-benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine to give thetitle compound.

PREPARATION 26

2-Methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl chloride

Combine 5-formylsalicylic acid (5.0 g, 30.1 mmol), potassium carbonate(16.6 g, 120.4 mmol), and methyl iodide (34.06 g, 240 mmol) in acetone(20 mL). Heat to reflux. After 12 hours, cool and extract five timeswith ethyl acetate. Combine the organic layers and extract with brine.Dry over MgSO₄, filter, and concentrate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with ethylacetate/hexane 1/1 to give methyl 2-methoxy-5-formylbenzoate: R_(f)=0.44(silica gel, 1/1 ethyl acetate/hexane).

Combine methyl 2-methoxy-5-formylbenzoate (0.1 g, 0.5 mmol) andtetrahydrofuran (2 mL). Cool in an ice bath. Add a solution of boranetetrahydrofuran complex (0.17 mL, 1 M in tetrahydrofuran, 0.17 mmol).After 1.5 hours, again add a solution of borane tetrahydrofuran complex(0.17 mL, 1 M in tetrahydrofuran, 0.17 mmol). After 2 hours, add a 1 Maqueous solution of hydrochloric acid (2 mL) and stir. After 15 minutes,dilute the reaction mixture with ethyl acetate. Separates the layers,extract the aqueous layer three times with ethyl acetate and combine theorganic layers. Dry the organic layer over Na₂SO₄, filter, and evaporatein vacuo to give methyl 2-methoxy-5-hydroxymethylbenzoate: R_(f)=0.32(silica gel, ethyl acetate).

Combine methyl 2-methoxy-5-hydroxymethylbenzoate (1.34 g, 6.8 mmol) andN,N-diisopropylethylamine (1.4 mL) in dichloromethane (25 mL). Cool in aice-bath. Add dropwise, methanesulfonyl chloride (0.56 mL). After 30minutes, warm to ambient temperature. After 2 hours, dilute withdichloromethane and extract with 1 M hydrochloric acid solution and 5%sodium bicarbonate solution. Dry the organic layer over Na₂SO₄, filter,and concentrate in vacuo to give methyl2-methoxy-5-chloromethylbenzoate: R_(f)=0.64 (silica gel, 1/1 ethylacetate/hexane).

Combine tetrazole (0.45 g, 6.42 mmol) and dimethylformamide (6 mL). Coolin an ice bath and add sodium hydride (0.26 g, 60% i oil, 6.5 mmol).After 30 minutes, warm to ambient temperature. Add a solution of methyl2-methoxy-5-chloromethylbenzoate (1.13 g, 4.12 mmol) indimethylformamide (10 (mL). Heat to 75° C. After 5.5 hours, partitionthe reaction mixture between water and ethyl acetate. Extract theorganic layer with water, dry over Na₂SO₄, filter, and concentrate invacuo to give a residue. Chromatograph the residue on silica gel elutingwith 7/3 hexane/ethyl acetate to give methyl2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoate: R_(f)=0.67 (silica gel,ethyl acetate).

Combine methyl 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoate (0.45 g,1.73 mmol) and methanol/tetrahydrofuran (1/1, 10 mL). Add a 1 M aqueoussolution of lithium hydroxide (5.8 mL, 5.8 mmol). After 4 hours,partition the reaction mixture between water and ethyl acetate. Acidifythe aqueous with a 10% aqueous citric acid solution, extract four timeswith ethyl acetate, combine the ethyl acetate layers, dry the organiclayer over Na₂SO₄, filter, and evaporate in vacuo to give2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid: R_(f)=0.60 (silicagel, 1/1 methanol/dichloromethane).

Combine 2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoic acid (0.35 g, 1.5mmol) and dichloromethane (25 mL). Add dropwise oxalyl chloride (0.21mL, 2.35 mmol) followed by dimethylformamide (5 drops). After 4 hours,evaporate in vacuo and dry to give the title compound.

EXAMPLE 64

1-(2-Methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxthetyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

64.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.69 g, 1.49 mmol) and sodiumbicarbonate (0.93 g, 11.07 mmol) in acetone/water (1/1, 40 mL). Cool inan ice bath. Add a solution of2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl chloride (0.38 g, 1.49 mmol)in acetone (25 mL). After 18 hours, dilute the reaction mixture withethyl acetate and extract twice with a saturated aqueous sodiumbicarbonate solution and then brine. Dry the organic layer over Na₂SO₄,filter, and concentrate invacuo to give a residue. Chromatograph theresidue on silica gel eluting with ethyl acetate and thenmethanol/dichloromethane/concentrated aqueous ammonia 10/90/0.1 give thetitle compound: R_(f)=0.82 (silica gel,methanol/dichloromethane/concentrated aqueous ammonia 10/90/0.1).

64.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-(1H-tetrazol-1H-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.35 g, 0.52 mmol) and dichloromethane (10 mL). Cool in an ice bath andadd a solution of hydrochloric acid in dioxane (0.26 mL, 4 M, 1.04mmol). After 15 minutes, evaporate in vacuo to give the title compound.

PREPARATION 27

2-Methoxy-5-(1H-triazol-1-ylmethyl)benzoyl chloride

Combine triazole (0.72 g, 10.4 mmol) and dimethylformamide (6 mL). Coolin an ice bath and add sodium hydride (0.42 g, 60% i oil, 10.4 mmol).After 30 minutes, warm to ambient temperature. Add a solution of methyl2-methoxy-5-chloromethylbenzoate (1.85 g, 6.74 mmol) indimethylformamide (6 mL). Heat to 75° C. After 3 hours, partition thereaction mixture between water and ethyl acetate. Extract the organiclayer with water, dry over Na₂SO₄, filter, and concentrate in vacuo togive a residue. Chromatograph the residue on silica gel eluting with95/5 dichloromethane/methanol containing 0.5% concentrated aqueousammonia to give methyl 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoate:R_(f)=0.l (silica gel, 1/1 hexane/ethyl acetate).

Combine methyl 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoate (1.14 g, 4.61mmol) and methanol/tetrahydrofuran (1/1, 30 mL). Add a 1 M aqueoussolution of lithium hydroxide (15 mL, 15 mmol). After 4 hours, acidifythe reaction mixture with a 10% aqueous citric acid solution, add water,and extract twice with ethyl acetate. Combine the organic layers, dryover Na₂SO₄, filter, and evaporate in vacuo to give2-methoxy-5-(1H-triazol-1-ylmethyl)benzoic acid: R_(f)=0.09 (silica gel,ethyl acetate).

Combine 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoic acid (0.22 g, 0.94mmol) and dichloromethane (50 mL). Add dropwise oxalyl chloride (0.14mL, 1.6 mmol) followed by dimethylformamide (5 drops). After 4 hours,evaporate in vacuo and dry to give the title compound.

EXAMPLE 65

1-(2-Methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

65.1 Synthesis of1-(2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3--(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.48 g, 1.04 mmol), N,N-diisopropylethylamine (0.35 mL), and2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl chloride (0.22 g, 0.94 mmol)in tetrahydrofuran (50 mL). After 18 hours, dilute the reaction mixturewith ethyl acetate and extract with a saturated aqueous sodiumbicarbonate solution and then brine. Dry the organic layer over Na₂SO₄,filter, and concentrate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with methanol/dichloromethane/concentratedaqueous ammonia 10/90/0.5 give the title compound: R_(f)=0.68 (silicagel, methanol/dichloromethane/concentrated aqueous ammonia 10/90/0.1).

65.2 Synthesis of1-(2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 64.2 using1-(2-methoxy-5-(1H-triazol-1-ylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.28 g, 0.49 mmol) to give the title compound.

PREPARATION 28

4-(1-(2-(1H-Imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHydriodic acid salt

Combine1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(1.0 g, 2.77 mmol), N,N-diisopropylethylamine (0.79 g, 6.1 mmol), anddichloromethane (10 mL). Cool in an ice bath. Add dropwisemethanesulfonyl chloride (0.41 g, 3.6 mmol). After 1 hour, warm toambient temperature and dilute the reaction mixture withdichloromethane. Extract with a 1 M aqueous hydrochloric acid solutionand three times with saturated aqueous sodium bicarbonate solution. Drythe organic layer over Na₂SO₄, filter, and concentrate in vacuo to give1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.58 (silica gel, ethyl acetate).

Combine imidazole (0.08 g, 1.2 mmol) and dimethylformamide (2 mL). Coolin an ice bath and add sodium hydride (0.04 g, 60% i oil, 1.2 mmol).After 30 minutes, warm to ambient temperature. Add a solution of1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.35 g, 0.80 mmol) in dimethylformamide (2 mL). Heat to 75° C. After 12hours, partition the reaction mixture between water and dichloromethane.Extract the organic layer twice with water, dry over Na₂SO₄, filter, andconcentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 5% methanol/dichloromethane/0.5% concentratedaqueous ammonia to give1-(t-butoxycarbonyl)-4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.44 (silica gel, 5% methanol/dichloromethane/0.5% concentratedaqueous ammonia).

Combine1-(t-butoxycarbonyl)-4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.22 g, 0.54 mmol), 57% hydriodic acid (0.25 mL, 1.13 mmol), methanol(10 mL) and heat to reflux. After 20 hours, cool the reaction mixtureand evaporate in vacuo to give a residue. Triturate the residue withdiethyl ether to give a solid. Repeatedly, decant and add diethyl etherbefore collecting the solid by filtration, rinse with diethyl ether, anddry in vacuo to give the title compound.

EXAMPLE 66

1-(3,4,5-Trimethoxybenzoyl)-3-2-(4-(1-(2-1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

66.1 Synthesis of1-(3,4,5-trimethoxybenzoyl-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.34 g, 0.60 mmol),4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt (0.27 g, 0.60 mmol), and N,N-diisopropylethylamine(0.31 g, 2.39 mmol) in acetonitrile (10 mL). Heat to reflux. After 12hours, cool to ambient temperature and dilute the reaction mixture withdichloromethane and extract with twice water. Dry the organic layer overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with 10% methanol/dichloromethane/0.5%concentrated aqueous ammonia) to give the title compound: R_(f)=0.32(silica gel, 10% methanol/dichloromethane/0.5% concentrated aqueousammonia).

66.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.26 g, 0.39 mmol) and methanol (10 mL). Add a solution of hydrochloricacid in dioxane (0.195 mL, 4 M, 0.78 mmol). heat to reflux. After 1hour, evaporate in vacuo to give a residue. Triturate the residue withdiethyl ether (50 mL) and stir to give a solid. After 12 hours, decantthe solvent and collect the solid to give the title compound.

PREPARATION 29

4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHydriodic acid salt

Prepare by the method of Preparation 28 using triazole (0.045 g, 1.13mmol) and1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.33 g, 0.75 mmol) to give1-(t-butoxycarbonyl)-4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.32 (silica gel, 5% methanol/dichloromethane/0.5% concentratedaqueous ammonia).

Prepare the method of Preparation 28 using1-(t-butoxycarbonyl)-4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.22 g, 0.54 mmol) the title compound.

EXAMPLE 67

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

67.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 66.1 using1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.25 g, 0.54 mmol),4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt (0.31 g, 0.54 mmol) to give the title compound:R_(f)=0.41 (silica gel, 10% methanol/dichloromethane/0.5% concentratedaqueous ammonia).

67.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 66.2 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-triazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.31 g, 0.46 mmol) to give the title compound.

PREPARATION 30

4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHydriodic acid salt

Combine1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(1.0 g, 2.77 mmol), triphenylphosphine (0.73 g, 2.78 mmol), andtetrazole (0.24 g, 3.38 mmol) in tetrahydrofuran (25 mL). Add a solutionof diethylazodicarboxylate (0.59 g, 3.38 mmol) in tetrahydrofuran (1mL). After 12 hours, concentrate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane to give1-(t-butoxycarbonyl)-4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.57 (silica gel, 1/1 hexane/ethyl acetate).

Combine1-(t-butoxycarbonyl)-4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(2.06 g) and methanol (15 mL). Add a solution of hydrochloric acid indioxane (4 mL, 4 M, 16 mmol) and stir. After 4 hours, add a 1 M aqueoussolution of sodium hydroxide until the pH is about 14. Concentrate invacuo to remove most of the methanol and then extract 5 times withdichloromethane. Dry the combined organic layers over Na₂SO₄, filter,and concentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 10% methanol/dichloromethane/0.5% concentratedaqueous ammonia to give4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.30 (silica gel, 10% methanol/dichloromethane/0.5% concentratedaqueous ammonia).

Combine4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.30 g, 0.96 mmol) and methanol (10 mL). Add hydriodic acid (0.27 mL,57%, 2.02 mmol). After 2 hour, evaporate in vacuo to give a residue.Triturate the residue with diethyl ether (about 20 mL) to give a solid.Collect the solid and dry to give the titlecompound.

EXAMPLE 68

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

68.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.34 g, 0.72 mmol),4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt (0.41 g, 0.72 mmol), and N,N-diisopropylethylamine(0.33 g, 2.53 mmol) in acetonitrile (10 mL). Heat to reflux. After 12hours, cool to ambient temperature and dilute the reaction mixture withdichloromethane and extract with twice water. Dry the organic layer overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with 5% methanol/dichloromethane/0.5%concentrated aqueous ammonia). Combine the product containing fractions,evaporate in vacuo, dissolve in dichloromethane, and extract with water,dry over Na₂SO₄, filter, and evaporate invacuo to to give the titlecompound: R_(f)=0.30 (silica gel, 5% methanol/dichloromethane/0.5%concentrated aqueous ammonia).

68.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineHydriodic acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(1H-tetrazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.33 g, 0.48 mmol) and methanol (10 ml). Add hydriodic acid (0.13 mL,57%, 1.0 mmol). After 4 hour, evaporate in vacuo to give a residue.Triturate the residue with diethyl ether (about 20 mL) and stir to givea solid. Collect the solid and dry to give the title compound.

EXAMPLE 69

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

69.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.1 g, 0.17 mmol) and dimethylformamide (2 mL). Add sodium hydride (8mg, 60% in oil, 0.34 mmol). After 12 hours, add 1-bromo-4-cyanobutane(27 mg, 0.17 mmol). After 1.5 hours, add water (5 mL) anddichloromethane (20 mL). Separate the layers and extract the aqueouslayer twice with dichloromethane. Combine the organic layers, dry overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with 5% methanol/dichloromethane/0.5%concentrated aqueous ammonia to give the title compound: R_(f)=0.26(silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueousammonia).

69.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.12 g, 0.19 mmol) and methanol (10 mL). Add a solution of hydrochloricacid in dioxane (0.093 mL, 4 M, 0.37 mmol) and stir. After 12 hours,evaporate in vacuo to give a residue. Triturate the residue with diethylether (about 20 mL) to give a solid. Three times, decant the solvent andadd diethyl ether. Collect the solid and dry to give the title compound.

EXAMPLE 70

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-(1H-tetrazol-5-yl)butyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

70.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-(1H-tetrazol-5-yl)butyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.45 g, 0.67 mmol), sodium azide (0.13 g, 2.04 mmol), andtriethylammonium hydrochloride (0.14 g, 1.03 mmol) inN-methylpyrrolidinone (6 mL). Heat to 150° C. After 4 hours, cool toambient temperature and partition the reaction mixture between water andethyl acetate. Separate the layers and extract the aqueous layer threetimes with ethyl acetate. Adjust the pH of the aqueous layer to about 1using a 1 M aqueous hydrochloric acid solution. The aqueous layer isagain extracted three times with ethyl acetate, and twice withdichloromethane. The aqueous layer is saturated with sodium chloride andagain extracted four times with dichloromethane. Combine the organiclayers, dry over MgSO₄, filter, and evaporate in vacuo to give residue.Chromatograph the residue on silica gel eluting with 20%methanol/dichloromethane to give the title compound: R_(f)=0.33 (silicagel, 20% methanol/dichloromethane/0.5% concentrated aqueous ammonia).

PREPARATION 31

3-(1H-Tetrazol-1-yl)benzoic acid

Prepare by the method of Preparation 11 using ethyl 3-aminobenzoate togive ethyl 3-(1H-tetrazol-1-yl)benzoate: R_(f)=0.51 (silica gel, 1/1ethyl acetate/hexane).

Combine ethyl 3-(1H-tetrazol-1-yl)benzoate (4.93 g, 22.6 mmol) andtetrahydrofuran/water (100 mL/25 mL). Add lithium hydroxide (1.9 g, 45.2mmol) and heat to reflux. After 2 hours, cool to ambient temperature andextract the reaction mixture five times with a 1 M aqueous sodiumhydroxide solution. Combine the aqueous layers and extract with ethylacetate. Acidify the aqueous layers with a 1 M aqueous hydrochloric acidsolution (pH about 1) to give a solid. Collect the solid by filtrationto give the title compound.

EXAMPLE 71

1-(3-(1H-Tetrazol-1-yl)benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl-3-phenylpyrrolidine

71.1 Synthesis of1-3-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using 3-(1H-tetrazol-1-yl)benzoicacid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 32.1

2-Methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoic acid

According to the method of Tet. Let., 26, 1661 (1985), combine methyl2-methoxy-5-aminobenzoate (0.5 g, 2.76 mmol) and di-2-pyridylthionocarbonate (0.64 g, 2.76 mmol) in dichloromethane (10 mL). After 30minutes, dilute the reaction mixture with dichloromethane and extractfive times with water. Dry the organic layer over Na₂SO₄, filter, andconcentrate in vacuo to give methyl 2-methoxy-5-isothiocyanatobenzoate:R_(f)=0.51 (silica gel, dichloromethane).

Combine methyl 2-methoxy-5-isothiocyanatobenzoate (0.61 g, 2.71 mmol),sodium azide (0.25 g, 3.87 mmol), ammonium chloride (0.23 g, 4.35 mmol)in water (10 mL). Heat to 70° C. After 2 hours, cool to ambienttemperature and acidify to pH about 1 using a 1 M aqueous hydrochloricacid solution to give a solid. Collect the solid by filtration to givemethyl 2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate: R_(f)=0.45 (silicagel, 1/1 ethyl acetate/hexane).

Combine methyl 2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate, methyliodide (1.2 g, 8.45 mmol), N,N-diisopropylethylamine (1.09 g, 8.45 mmol)and dichloromethane (75 mL). After 20 hours, extract the reactionmixture twice with a saturated aqueous ammonium chloride solution. Drythe organic layer over Na₂SO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 1%acetone/dichloromethane to give methyl2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate: R_(f)=0.43 (silicagel, 1% acetone/dichloromethane).

Combine methyl 2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate (0.35g, 1.23 mmol) and dichloromethane (20 mL). Add m-chloroperbenzoic acid(1.06 g, 50%, 3.1 mmol). After 2 hour, filter and dilute the reactionmixture with dichloromethane. Extract with a 1 M aqueous solution ofsodium hydroxide. Dry the organic layer over Na₂SO₄, filter, andconcentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 0.1% acetone/dichloromethane to give a methyl2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoate.

Combine methyl 2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoate(5 mmol), methanol (10 mL), and a 1 M aqueous sodium hydroxide solution(6 mL, 6.0 mmol). After 18 hours, evaporate in vacuo to give a residue.Combine the residue, water (5 mL) and acidify by dropwise addition of a1 M aqueous hydrochloric acid solution (6.5 mL). Evaporate in vacuo togive a residue. Combine the residue and dichloromethane and stir. Decantand add dichloromethane and stir. Decant and combine with the firstdecantate. Dry over Na₂SO₄, filter, and concentrate in vacuo to give thetitle compound.

PREPARATION 32.2

2-Methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoic acid

Combine methyl 2-methoxy-5-isothiocyanatobenzoate (4.0 g, 17.9 mmol),sodium azide (1.4 g, 21.5 mmol), ammonium chloride (1.4 g, 26.2 mmol) inwater (70 mL). Heat to 70° C. After 4 hours, cool to ambient temperatureand acidify to pH about 1 using a 1 M aqueous hydrochloric acid solutionto give a solid. Collect the solid by filtration to give methyl2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate.

Combine methyl 2-methoxy-5-(5-thio-1H-tetrazol-1-yl)benzoate obtainedabove, methyl iodide (1 mL), N,N-diisopropylethylamine (3 mL) anddichloromethane (100 mL). After 12 hours, extract the reaction mixturetwice with a saturated aqueous ammonium chloride solution. Dry theorganic layer over Na₂SO₄, filter, and evaporate invacuo to give aresidue. Chromatograph the residue on silica gel eluting with 2%acetone/dichloromethane to give methyl2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate.

Combine methyl 2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoate (0.51g, 1.81 mmol) and lithium hydroxide (0.065 g, 2.71 mmol) andtetrahydrofuran/water (5 mL/5 mL). Heat to reflux. After 1 hour, cool toambient temperature, separate the layers, and extract the organic layer2 times with 1 M aqueous sodium hydroxide solution. Combine the aqueouslayers and extract with diethyl ether. Acidify the aqueous layer usingaqueous 1 M hydrochloric acid solution to give the title compound.

EXAMPLE 72.1

1-(2-Methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

72.1.1 Synthesis of1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl-benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

EXAMPLE 72.2

1-(2-Methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

72.2.1 Synthesis of1-(2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

72.2.2 Synthesis of1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine

Combine1-(2-methoxy-5-(5-methylthio-1H-tetrazol-1-yl)benzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine(0.55 g, 1.25 mmol) and dichloromethane (20 mL). Add m-chloroperbenzoicacid (1.04 g, 50%, 3.0 mmol) and potassium carbonate (0.41 g). After 2hour, filter and dilute the reaction mixture with dichloromethane.Extract three times with a 1 M aqueous solution of sodium hydroxide. Drythe organic layer over Na₂SO₄, filter, and concentrate in vacuo to givea residue. Chromatograph the residue on silica gel eluting with 5%methanol/dichloromethane to give the title compound: R_(f)=0.36 (silicagel, 5% methanol/dichloromethane).

72.2.3 Synthesis of1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine

Prepare by the method of Example 2.5.2 using1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-hydroxyethyl)-3-phenylpyrrolidine(0.41 g, 0.87 mmol) to give the title compound: R_(f)=0.69 (silica gel,5% methanol/dichloromethane).

72.2.4 Synthesis of1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-methanesulfonyloxyethyl)-3-phenylpyrrolidine(0.44 g, 0.81 mmol), triethylamine (0.33 g, 3.23 mmol), and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.44 g, 8.1 mmol) in acetonitrile (10 mL). Heat to reflux. After12 hours, cool the reaction mixture, dilute with dichloromethane, andextract with water. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 5% methanol/dichloromethane to give the titlecompound.

72.2.4 Synthesis of1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.31 g, 0.41 mmol) and ethyl acetate (10 mL). Add a solution ofhydrochloric acid in dioxane (0.216 mL, 4 M, 0.87 mmol). Heat to reflux.After 30 minutes, cool to ambient temperature and add diethyl ether (80mL) to give a solid. Collect the solid by filtration and dry to give thetitle compound.

PREPARATION 33

2-Methyl-5-(1H-tetrazol-1-yl)benzoic acid

Combine 2-methyl-5-nitrobenzoic acid (4.98 g, 27.5 mmol), potassiumcarbonate (1.93 g, 14.0 mol), and methyl iodide (7.80 g, 55.0 mmol) inacetone (100 mL). Heat to reflux. After 4 hours, cool the reactionmixture, dilute with water, and extract five times with ethyl acetate.Combine the organic layers, extract with a saturated aqueous sodiumbicarbonate solution and then brine. Dry the organic layer over Na₂SO₄,filter, and evaporate in vacuo to give methyl 2-methyl-5-nitrobenzoate:R_(f)=0.61 (silica gel, ethyl acetate/hexane 1/1).

Combine methyl 2-methyl-5-nitrobenzoate (5.32 g, 27.2 mmol) and methanol(100 mL). Add 5% palladium-on-carbon (0.27 g). Hydrogenate on a pressureapparatus at 50 psi. After 18 hours, filter through celite to remove thecatalyst and evaporate the filtrate in vacuo to give methyl2-methyl-5-aminobenzoic acid: R_(f)=0.34 (silica gel, ethylacetate/hexane 1/4).

Combine methyl 2-methyl-5-aminobenzoate (4.5 g, 27.2 mmol) and triethylorthoformate (16.2 g, 109 mmol) in glacial acetic acid (25 mL). After 12hours, add portionwise sodium azide (7.08 g, 109 mmol). Heat to 70° C.After 2 hours, cool the reaction mixture to ambient temperature, dilutewith water (250 mL). Collect the solid by filtration, rinse with water,and dry to give methyl 2-methyl-5-(1H-tetrazol-1-yl)benzoate: R_(f)=0.13(silica gel, ethyl acetate/hexane 1/4).

Combine methyl 2-methyl-5-(1H-tetrazol-1-yl)benzoate (5.2 g, 23.9 mmol)and lithium hydroxide hydrate (2.0 g, 47.7 mmol) intetrahydrofuran/water (50 mL/50 mL). Heat to reflux. After 2 hours,dilute with diethyl ether and separate the Layers. Extract the aqueouslayer three times with diethyl ether. Extract the combined diethyl etherlayers three times with a 1 M sodium hydroxide solution (20 mL). Combinethe aqueous layers, acidify with a 1 M aqueous hydrochloric acidsolution (pH about 1) to give a solid. Collect the solid by filtrationand recrystallize form water to give the title compound.

EXAMPLE 73

1-(2-Methyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

73.1 Synthesis of1-(2-methyl-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methyl-5-(1H-tetrazol-1-yl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 34

2-Methoxy-5-trifluoromethoxybenzoyl chloride

Combine 2-methoxy-5-trifluoromethoxybenzene (1.0 g, 5.2 mmol) andtrifluoroacetic acid (200 mL). Add slowly portionwisehexamethylenetetraamine (26 g, 185.7 mmol). Heat at 60° C. After 24hours, cool to ambient temperature and pour the reaction mixture into a2 M aqueous solution of sulfuric acid (500 mL). Cool and extract tentimes with diethyl ether. Dry the combined organic layers over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 1/4 ethyl acetate/hexane to give2-methoxy-5-trifluoromethoxybenzaldehyde.

According to the method of Heterocycles, 16, 2091 (1981), combine2-methoxy-5-trifluoromethoxybenzaldehyde (0.58 g, 2.65 mmol) and2-methylbut-2-ene (37 mL) in t-butanol (16 mL). Add dropwise a solutionof sodium dihydrogen phosphate hydrate (0.92 g) and sodium chlorite(0.42 g, 4.7 mmol) in water (10 mL). After 4 hours, adjust the pH of thereaction mixture to about 8 to 9 using a 1 M aqueous sodium hydroxidesolution. Evaporate the reaction mixture in vacuo at about ambienttemperature to remove most of the t-butanol. Add water (40 mL) andextract three times with hexane (10 mL). Adjust the pH of the aqueouslayer to about 1 using a 1 M aqueous hydrochloric acid solution andextract five times with diethyl ether. Combine the organic layers, dryover Na₂SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane containing 0.5% acetic acid to give2-methoxy-5-trifluoromethoxybenzoic acid: R_(f)=0.34 (silica gel, 1/1ethyl acetate/hexane containing 0.5% acetic acid).

Combine 2-methoxy-5-trifluoromethoxybenzoic acid (0.6 g, 2.53 mmol) anddichloromethane (10 mL). Cool in an ice bath. Add dropwise oxalylchloride (0.64 mL, 5.0 mmol) followed by dimethylformamide (1 drop).Warm to ambient temperature. After 3 hours, evaporate in vacuo and dryto give the title compound.

EXAMPLE 74

1-(2-Methoxy-5-trifluoromethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

74.1 Synthesis of1-(2-methoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine

Combine (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (1.7 g, 2.5 mmol) and sodiumcarbonate (1.32 g, 12.5 mmol) in ethyl acetate/water (1/1) (20 mL). Adda solution of 2-methoxy-5-trifluoromethoxybenzoyl chloride (0.64 g, 2.5mmol) in ethyl acetate (10 mL). After 14 hours, separate the organiclayer. Extract the aqueous layer four times with dichloromethane. Drythe combined organic layers over Na₂SO₄, filter, and concentrate invacuo to obtain a residue. Chromatograph the residue on silica geleluting with ethyl acetate to give the title compound: R_(f)=0.32(silica gel, ethyl acetate).

74.2 Synthesis of1-(2-methoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using1-(2-ethoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidineto give the title compound.

74.3 Synthesis of1-(2-methoxy-5-trifluoromethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 1.6 using1-(2-methoxy-5-trifluoromethylbenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

EXAMPLE 75

1-((R)-α-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-31-(4-fluorophenylmethyl)-2-oxopyrrolidine

75.1 Synthesis of 1-((R)-α-methylbenzyl)-2-oxopyrrolidine

According the the procedure of J. Am. Chem. Soc., 74, 1952 (1959),combine butyrolactone (8.6 g, 100 mmol) and (R)-α-methylbenzylamine(15.0 g, 123 mmol) and heat to 180° C. After 48 hours, heat to 210° C.After 6 hours, cool the reaction mixture and evaporate in vacuo using ashort path distillation apparatus to obtain a residue: bp 110° C. at 0.5mm Hg. Chromatograph the residue on silica gel eluting with ethylacetate to give the title compound: R_(f)=0.45 (silica gel, ethylacetate).

75.2 Synthesis of1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Combine 1-((R)-α-methylbenzyl)-2-oxopyrrolidine (1.0 g, 5.29 mmol) andtetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath.Add dropwise a solution of sec-butyllithium (4.5 mL, 1.3 M in hexane,5.8 mmol). After 30 minutes, slowly add a solution of 4-fluorobenzylbromide (1.1 g, 5.8 mmol). After 15 minutes, warm to ambienttemperature. After 3 hours, add water (10 mL). Separate the layers andextract the aqueous layer three times with ethyl acetate. Dry thecombined organic layers over Na₂SiO₄, filter, and evaporate in vacuo togive a residue. Chromatograph the residue on silica gel eluting with 1/4ethyl acetate/hexane to give diastereomers of the title compound:R_(f)=0.44 and 0.75 (silica gel, 1/1 ethyl acetate/hexane).

75.3 Synthesis of1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Prepare by the method of Example 25.2 using1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine to givethe title compound: R_(f)=0.55 (silica gel, 1/4 ethyl acetate/hexane).

75.4 Synthesis of1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine(1.7 g, 3.73 mmol) and ammonium fluoride (0.83 g, 22.4 mmol) to give,after chromatography on silica gel eluted with 1/1 ethyl acetate/hexane,the title compound as diastereomers: R_(f)=0.51 and 0.25 (silica gel,1/1 ethyl acetate/hexane).

75.5 Synthesis of1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine(R_(f)=0.51 silica gel, 1/1 ethyl acetate/hexane) to give a diastereomerof the title compound: R_(f)=0.75 (silica gel, ethyl acetate).

Prepare by the method of Example 2.5.2 using1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine(R_(f)=0.25 silica gel, 1/1 ethyl acetate/hexane) to give a diastereomerof the title compound: R_(f)=0.55 (silica gel, ethyl acetate).

75.6 Synthesis of1-((R)-α-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Combine1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine(R_(f)=0.75 silica gel, ethyl acetate) (0.44 g, 1.04 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.49 g, 1.04 mmol), and N,N-diisopropylethylamine (0.54 g, 4.2mmol) in acetonitrile (10 mL). Heat to reflux. After 16 hours, cool andpartition the reaction mixture between dichloromethane and water.Separate the layers and extract the organic layer twice with water. Drythe organic layer over Na₂SO₄, filter, and concentrate in vacuo toobtain a residue. Chromatograph the residue on a short column of silicagel eluting with 2.5% methanol/dichloromethane/0.5% concentrated aqueousammonia to give a diastereomer of the title compound: R_(f)=0.60 (silicagel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia).

Combine1-((R)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine(R_(f)=0.55 silica gel, ethyl acetate) (0.77 g, 1.84 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.87 g, 1.84 mmol), and N,N-diisopropylethylamine (0.95 g, 4957.4mmol) in acetonitrile (10 mL). Heat to reflux. After 16 hours, cool anddilute the reaction mixture with dichloromethane. Extract twice withwater, dry over Na₂SO₄, filter, and concentrate in vacuo to obtain aresidue. Chromatograph the residue on a short column of silica geleluting with 2.5% methanol/dichloromethane/0.5% concentrated aqueousammonia to give a diastereomer of the title compound: R_(f)=0.46 (silicagel, 5% methanol/dichloromethane/0.5%6 concentrated aqueous ammonia).

75.7 Synthesis of1-((R)-α-methylbenzyl)-3-(2-(4-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidinehydrochloric acid salt

Combine1-((R)-α-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine(R_(f)=0.46 silica gel, 5% methanol/dichloromethane/0.5% concentratedaqueous ammonia) (0.71 g, 1.16 mmol) and methanol (10 mL). Add asolution of hydrochloric acid in dioxane (0.60 mL, 4 M, 2.4 mmol). After12 hours, evaporate the reaction mixture in vacuo to give a residue.Triturate the residue with diethyl ether (100 mL) and stir to give asolid. After 6 hours, collect the solid and dry to give the titlecompound.

EXAMPLE 76

1-((S)-α-Methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

76.1 Synthesis of 1-((S)-α-methylbenzyl)-2-oxopyrrolidine

Prepare by the method of Example 75.1 using (S)-α-methylbenzylamine togive the title compound: R_(f)=0.46 (silica gel, ethyl acetate).

76.2 Synthesis of1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 75.2 using1-((S)-α-methylbenzyl)-2-oxopyrrolidine (1.0 g, 5.29 mmol) to give,after chromatograph on silica gel eluting with 1/4 ethyl acetate/hexane,diastereomers of the title compound: R_(f)=0.46 and 0.70 (silica gel,1/1 ethyl acetate/hexane).

76.3 Synthesis of1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Prepare by the method of Example 75.3 using1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine to givethe title compound: R_(f)=0.51 (silica gel, 1/4 ethyl acetate/hexane).

76.4 Synthesis of1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine(1.7 g, 3.73 mmol) and ammonium fluoride (0.83 g, 22.4 mmol) to give,after chromatography on silica gel eluting with 1/1 ethyl acetate/hexaneto give the title compound as diastereomers: R_(f)=0.49 and 0.27 (silicagel, 1/1 ethyl acetate/hexane).

76.5 Synthesis of1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine(R_(f)=0.49 silica gel, 1/1 ethyl acetate/hexane) to give a diastereomerof the title compound: R_(f)=0.71 (silica gel, ethyl acetate).

Prepare by the method of Example 2.5.2 using1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine(R_(f)=0.27 silica gel, 1/1 ethyl acetate/hexane) to give a diasterebmerof the title compound: R_(f)=0.59 (silica gel, ethyl acetate).

76.6 Synthesis of1-((S)-α-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine

Combine1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyol)-2-oxopyrrolidine(R_(f)=0.71 silica gel, ethyl acetate) (0.45 g, 1.06 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.58 g, 1.06 mmol), and N,N-diisopropylethylamine (0.85 mL, 4.8mmol) in acetonitrile (10 mL). Heat to reflux. After 16 hours, cool andevaporate in vacuo to give a residue. Combine the residue and ethylacetate, extract twice with a saturated aqueous sodium bicarbonatesolution and then brine. Dry the organic layer over Na₂SO₄, filter, andconcentrate in vacuo to obtain a residue. Chromatograph the residue onsilica gel eluting sequentially with with 15% methanol/dichloromethaneand then 15% methanol/dichloromethane/1.0% concentrated aqueous ammoniato give a diastereomer of the title compound.

Combine1-((S)-α-methylbenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine(R_(f)=0.59 silica gel, ethyl acetate) (0.67 g, 1.59 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.86 g, 1.59 mmol), and N,N-diisopropylethylamine (1.24 mL, 7.13mmol) in acetonitrile (20 mL). Heat to reflux. After 16 hours, cool andevaporate in vacuo to give a residue. Combine the residue and ethylacetate, extract twice with a saturated aqueous sodium bicarbonatesolution and then brine. Dry the organic layer over Na₂SO₄, filter, andconcentrate in vacuo to obtain a residue. Chromatograph the residue onsilica gel eluting sequentially with with 15% methanol/dichloromethaneand then 15% methanol/dichloromethane/1.0% concentrated aqueous ammoniato give a diastereomer of the title compound.

76.7 Synthesis of1-((S)-α-methylbenzyl)-3-(2-(4-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidinehydrochloric acid salt

Combine1-((S)-α-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine(higher R_(f) diastereomer) (0.50 g, 0.80 mmol) and methanol (20 mL).Add a solution of hydrochloric acid in dioxane (0.50 mL, 4 M, 2.0 mmol).After 18 hours, evaporate the reaction mixture in vacuo to give aresidue. Triturate the residue with diethyl ether and stir to give asolid. Repeatedly, decant and add diethyl ether. Collect the solid anddry to give the title compound.

Combine1-((S)-α-methylbenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenylmethyl)-2-oxopyrrolidine(lower R_(f) diastereomer) (0.74 g, 1.18 mmol) and methanol (25 mL). Adda solution of hydrochloric acid in dioxane (0.74 mL, 4 M, 2.94 mmol).After 18 hours, evaporate the reaction mixture invacuo to give aresidue. Triturate the residue with diethyl ether and stir to give asolid. Repeatedly, decant and add diethyl ether. Collect the solid anddry to give the title compound.

EXAMPLE 77

1-(α-Methylbenzyl)-3-(2-(4-(1-(2ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-1-yl)ethyl)-3-phenylpyrrolidine

77.1 Synthesis1-(α-methylbenzy-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

According to the method of J. Am. Chem. Soc. , 93, 2897 (1971), combineacetophenone (10 mmol) and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)([1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) (10 mmol) in methanol (100 mL). Add bromocreosol green (0.5%by weight in methanol, 1 drop). Add dropwise, a solution of sodiumcyanoborohydride (10 mL, 1M in tetrahydrofuran, 10 mmol) and at the sametime maintain the pH of the reaction mixture, as indicated by a yellowcolor for the indicator, by the addition of a 5 M solution ofhydrochloric acid in methanol. When the reaction is complete,concentrate the reaction mixture in vacuo to obtain a residue. Dilutethe residue with ethyl acetate and extract with water. Separate thelayers, dry the organic layer over MgSO₄, filter, and evaporate in vacuoto give the title compound.

EXAMPLE 78

(R)-1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

78.1 Synthesis of(S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorphenyl)-3-(2-hydroxyethyl)pyrrolidine

Combine (S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt (1.20 g, 1.77 mmol) and sodiumbicarbonate (0.75 g, 9 mmol) in acetone/water (5 mL/5 mL). Cool in anice bath. Add 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (0.37 g,1.6 mmol) in acetone (20 mL). After 30 minutes, warm to ambienttemperature. After 5 hours, filter the reaction mixture and extract thefiltrate with ethyl acetate. Extract the organic layer with a saturatedaqueous sodium. bicarbonate solution and then brine. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give residue.Chromatograph the residue on silica gel eluting sequentially with ethylacetate, 3% methanol/dichloromethane, and then 6%methanol/dichloromethane to give the title compound: R_(f)=0.38 (silicagel, 6% methanol/dichloromethane).

78.2 Synthesis of(S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using(S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(0.6 g, 1.3 mmol) and methanesulfonyl chloride (0.12 mL, 1.2 mmol) togive the title compound: R_(f)=0.15 (silica gel, ethyl acetate).

78.3 Synthesis of(R)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Prepare by the method of Example 47.3 using(S)-1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodicacid salt to give the title compound.

PREPARATION 35

2-Methoxy-5-(methylthiomethyl)benzoic acid

Combine methyl 2-methoxy-5-chloromethylbenzoate (5 mmol) anddimethylformamide (10 mL). Cool in an ice bath and add sodiumthiomethoxide (15 mmol). Heat to 75° C. After 5.5 hours, partition thereaction mixture between water and ethyl acetate. Extract the organiclayer with water, dry over Na₂SO₄, filter, and concentrate in vacuo togive methyl 2-methoxy-5-(methylthiomethyl)benzoate.

Hydrolyze by the method of Preparation 22 to give the title compound.

EXAMPLE 79

1-(2-Methoxy-5-(methylthiomethylbenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

79.1 Synthesis of1-(2-methoxy-5-(methylthiomethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(methylthiomethyl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 36

2-Methoxy-5-(methylsulfinylmethyl)benzoic acid

Prepare by the method of Preparation 22 using methyl2-methoxy-5-(methylthiomethyl)benzoate to give the title compound.

EXAMPLE 80

1-(2-Methoxy-5-(methylsulfinylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

80.1 Synthesis of1-(2-methoxy-5-(methylsulfinylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(methylsulfinylmethyl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 37

2-Methoxy-5-(methylsulfonylmethyl)benzoic acid

Prepare by the method of Preparation 23 using methyl2-methoxy-5-(methylthiomethyl)benzoate to give the title compound.

EXAMPLE 81

1-(2-Methoxy-5-(methylsulfonylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

81.1 Synthesis of1-(2-methoxy-5-(methylsulfonylmethyl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(methylsulfonylmethyl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 38

2-Methoxy-5-(4H-triazol-4-yl)benzoic acid

According to the method of J. Chem. Soc. (C), 1664 (1967), combinemethyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol), N,N-dimethylformamideazine (1.56 g, 11 mmol), p-toluenesulfonic acid (190 mg) in toluene (25mL). Fit the reaction vessel with a gas inlet such that the head spaceof the vessel is swept with argon and scrub the effluent through diluteaqueous hydrochloric acid solution. Heat to reflux. After 20 hours,concentrate the reaction mixture in vacuo to give a residue. Partitionthe residue between dichloromethane and a saturated aqueous sodiumbicarbonate solution. Extract the aqueous layer twice withdichloromethane. Combine the organic layers, dry over MgSO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting sequentially with 70% ethyl acetate/dichloromethaneand then 5% methanol/dichloromethane to give a residue. Recrystallizethe residue form ethyl acetate/hexane to give methyl2-methoxy-5-(4H-triazol-4-yl)benzoate: mp; 191-195.5° C.

Hydrolyze methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate by the method ofPreparation 11 to give the title compound.

Alternately, according to the method of J. Med. Chem., 21, 1100 (1978),combine methyl 2-methoxy-5-aminobenzoate (1.8 g, 10 mmol), diformylhydrazine (0.97 g, 11 mmol), and phosphorous pentoxide (1.84 g, 13mmol). Heat to 160° C. After 1.5 hours, cool the reaction mixture andadd a saturated aqueous solution of sodium bicarbonate. Extract threetimes with dichloromethane. Dry the combined organic layers over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting sequentially with 40% ethylacetate/dichloromethane and then 5% methanol/dichloromethane to givemethyl 2-methoxy-5-(4H-triazol-4-yl)benzoate: mp; 179-182° C.

Hydrolyze 2-methoxy-5-(4H-triazol-4-yl)benzoate by the method ofPreparation 11 to give the title compound.

EXAMPLE 82

1-(2-Methoxy-5-(4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

82.1 Synthesis of1-(2-methoxy-5-(4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(4H-triazol-4-yl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give, after chromatography on silica gel elutingsequentially with 10% methanol/ethyl acetate and then 50% methanol/ethylacetate, the title compound.

82.2 Synthesis of1-(2-methoxy-5-4H-triazol-4-yl)benzoy)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-(4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.26 g, 0.38 mmol) and methanol (8 mL). Add a solution of hydrochloricacid in dioxane (0. 19 mL, 4 M, 0.77 mmol). After 18 hours, evaporate invacuo and then repeatedly add dichloromethane (about 15 mL), andevaporate in vacuo to give a solid. Combine the solid dichloromethane(40 mL) and evaporate until a solid begins to form and then add diethylether to give a solid. Collect the solid by filtration and dry to givethe title compound: mp; 176-190° C. (dec).

PREPARATION 39

2-Methoxy-5-acetamidobenzoic acid

Combine methyl 2-methoxy-5-aminobenzoate (2.0 g, 11 mmol), pyridine, 2.8mL, 35 mmol), and acetic anhydride (3.2 mL, 34 mmol) in tetrahydrofuran(50 mL). After 20 hours, concentrate the reaction mixture in vacuo toremove most of the tetrahydrofuran, partition between ethyl acetate andwater. Separate the layers and extract the aqueous layer twice withethyl acetate. Combine the organic layers, extract with brine, dry overMgSO₄, filter, and evaporate in vacuo to give a residue. Crystallize theresidue from ethyl acetate/cyclohexane to give methyl2-methoxy-5-acetamidobenzoate.

Alternately, combine methyl 2-methoxy-5-aminobenzoate (1.5 g, 8.3 mmol)and dichloromethane (25 mL). Cool in an ice bath. AddN,N-diisopropylethylamine (3.2 mL, 18.2 mmol), and acetyl chloride (0.62mL, 9.7 mmol). Warm to ambient temperature. After 4 hours, dilute thereaction mixture with dichloromethane and extract three times with halfsaturated aqueous ammonium chloride solution. Dry the organic layer overNa₂SO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting with 3% methanol/dichloromethane/0.1%concentrated aqueous ammonia to give methyl2-methoxy-5-acetamidobenzoate: mp; 132-134° C. Elemental Analysiscalculated for C₁₁H₁₃NO₄: C, 59.19; H, 5.87. Found C, 59.04; H, 5.86.

Hydrolyze methyl 2-methoxy-5-acetamidobenzoate by the method ofPreparation 24 to give the title compound: mp; 208-210° C.

EXAMPLE 83

1-(2-Methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

83.1 Synthesis of1-(2-methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using 2-methoxy-5-acetamidobenzoicacid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt(prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound:R_(f)=0.18 (silica gel, 1/1 ethylacetate/methanol).

83.2 Synthesis of1-(2-methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-acetamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.17 g, 0.26 mmol) and dichloromethane/methanol (3/1, 10 mL). Add asolution of hydrochloric acid in dioxane (0.065 mL, 4 M, 0.26 mmol)After 18 hours, evaporate in vacuo to give a residue. Triturate theresidue with diethyl ether and stir to give a solid. collect the solidby filtration to give the title compound: mp; 145-150° C.

PREPARATION 40

2-Methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid

Combine methyl 2-methoxy-5-acetamidobenzoate (2.23 g, 10 mmol) andtetrahydrofuran (1000 mL). Add Lawesson's reagent (2.02 g, 5 mmol).After 18 hours, evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 12% ethyl acetate/dichloromethane togive methyl 2-methoxy-5-thioacetamidobenzoate.

According to the method of Heterocycles, 34, 771 (1992), combine methyl2-methoxy-5-thioacetamidobenzoate (1.00 g, 4.2 mmol) and acetylhydrazine(0.35 g, 4.8 mmol) in n-butanol (8 mL). Heat to reflux. After 18 hours,cool and evaporate in vacuo to give a residue. Chromatograph the residueon silica gel eluting sequentially with 30% ethylacetate/dichloromethane and then 5% methanol/dichloromethane to give aresidue. Recrystallize the residue from ethyl acetate/hexame to givemethyl 2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoate: mp; 180-182°C.

Hydrolyze the methyl 2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoateby the method of Preparation 11 to give the title compound: mp; 206-207°C.

EXAMPLE 84

1-(2-Methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

84.1.1 Synthesis of1-(2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

84.1.2 Synthesis of1-(2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) (0.64 g, 1.2 mmol) and dichloromethane (12 mL). Add2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoic acid (0.3 g, 1.2mmol), 1-hydroxybenzotriazole hydrate (0.17 g, 1.23 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.29 g, 1.5mmol), and triethylamine (0.34 mL, 2.4 mmol). After 6 days, dilute thereaction mixture with dichloromethane and extract with a saturatedaqueous sodium bicarbonate solution and then brine, dry the organiclayer over MgSO₄, filter, and concentrate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially with 10%methanol/dichloromethane and then 20% methanol/dichloromethane to give aresidue. Combine the residue and dichloromethane, extract with water andthen brine, dry over Na₂SO₄, and evaporate in vacuo to give the titlecompound.

84.2 Synthesis of1-(2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 82.2 using1-(2-methoxy-5-(3,5-dimethyl-4H-triazol-4-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 41

2-Methoxy-5-methylsulfonamidobenzoic acid

Combine methyl 2-methoxy-5-aminobenzoate (1.5 g, 8.3 mmol) anddichloromethane (25 mL). Cool in an ice bath. AddN,N-diisopropylethylamine (3.17 mL, 18.2 mmol) and methanesulfonylchloride (0.71 mL, 9.1 mmol). After 30 minutes, warm to ambienttemperature. After 4 hours, dilute the reaction mixture withdichloromethane and extract three times with a 1 M aqueous hydrochloricacid solution and then brine. Dry the organic layer over Na₂SO₄, filter,and evaporate in vacuo to give a residue.

Chromatograph the residue on silica gel eluting with 3%methanol/dichloromethane/0.1% concentrated aqueous ammonia to givemethyl 2-methoxy-5-methylsulfonamidobenzoate: mp; 82-83° C. ElementalAnalysis calculated for C₁₀H₁₃NO₅S: C, 46.32; H. 5.05; N, 5.40. Found C,46.44; H, 4.96; N, 5.19.

Combine methyl 2-methoxy-5-methylsulfonamidobenzoate (1.0 g, 3.86 mmol)and lithium hydroxide (93 mg, 3.86 mmol) in tetrahydrofuran/water (50mL/10 mL). After 18 hours, add lithium hydroxide (100 mg) and heat toreflux. After 1 hour, cool to ambient temperature and evaporate toremove most of the tetrahydrofuran. Dilute the evaporated reactionmixture with water (about 70 mL) and acidify to pH of about 1 using a 1M aqueous hydrochloric acid solution. Evaporate to dryness and trituratewith dichloromethane (200 mL). Filter and evaporate the filtrate to givethe title compound: mp; 160-163° C.

EXAMPLE 85

1-(2-Methoxy-5-methylsulfonamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

85.1 Synthesis of1-(2-methoxy-5-methylsulfonamidobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-methylsulfonamidobenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 42

2-Methoxy-5-fluorobenzoic acid

Combine 5-fluorosalicylic acid (5.00 g, 32 mmol), finely groundpotassium carbonate (15.0 g, 108 mmol), and methyl iodide (34.2 g, 240mmol) in acetone (100 mL). Heat to reflux. After 18 hours, cool, filter,and evaporate in vacuo to give a residue. Combine the residue anddichloromethane and extract twice with water, dry over Na₂SO₄, filter,and concentrate in vacuo to give methyl 2-methoxy-5-fluorobenzoate.Elemental Analysis calculated for C₉H₉FO₃: C, 58.70; H, 4.93. Found C,58.72; H, 5.12.

Hydrolyze methyl 2-methoxy-5-fluorobenzoate by the method of Preparation11 to give the title compound.

EXAMPLE 86

1-(2-Methoxy-5-fluorobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

86.1 Synthesis of1-(2-methoxy-5-fluorobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using 2-methoxy-5-fluorobenzoicacid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 43

3,4-Dimethoxy-5-ethoxybenzoic acid

Combine 3,4-dimethoxy-5-hydroxybenzoic acid (1.0 g, 5.0 mmol), potassiumcarbonate (4.2 g, 30.2 mmol), and ethyl iodide (3.9 g, 25.2 mmol) inacetone (50 mL). Heat to reflux. After 24 hours, cool, add methanol (25mL) and water (5 mL) After 18 hours, concentrate in vacuo to give aresidue. Combine the residue and ethanol (50 mL) and potassium hydroxide(0.56 g, 10 mmol). After 18 hours, concentrate in vacuo to give aresidue. Partition the residue between ethyl acetate and a 1 M aqueoussolution of hydrochloric acid. Extract the aqueous layer three timeswith ethyl acetate. Combine the organic layers, dry over Na₂SO₄, filter,and concentrate in vacuo to give a residue. Triturate the residue togive a solid. Collect the solid to give the title compound.

EXAMPLE 87

1-(3,4-Dimethoxy-5-ethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using3,4-dimethoxy-5-ethoxybenzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

EXAMPLE 88

(S)-1-(34,5-Trimethoxybenzoyl)-3-(2-(4-(1-2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl-3-(3,4-dichlorophenyl)pyrrolidine

88.1 Resolution of(R)-(+)-3-(3,4-dichlorophenyl-3-(2-hydoxyethyl)pyrrolidine(S,S)-di-p-anisoyltartaric acid salt

Combine (S,S)-di-p-anisoyltartaric acid (14.77 g, 35 mmol), water (200mL) and methanol (200 mL). Heat to reflux. Add dropwise, a solution of3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine (18.36 g, 70 mmol)in methanol (135 mL). After 1.5 hours, add water (135 mL) and slowlycool to ambient temperature to give a solid. Filter the solid that formsand rinse with water to give the title compound: mp; 201-202° C. (dec).Analysis by HPLC, as described in Example 5.1.1 indicates anenantiomeric excess of 99.9%, (99.9% ee). [α]² _(D) ⁰=+17.9° (c=1.00,dimethylsulfoxide)

88.2 Synthesis of(R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 5.2.2 using(R)-(+)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine(S,S)-di-p-anisoyltartaric acid salt to give the title compound:R_(f)=0.29 (silica gel, 6% methanol/dichloromethane).

88.3 Synthesis of(R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using(R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.33 (silica gel, ethyl acetate) andR_(f)=0.44 (silica gel, 6% methanol/dichloromethane).

88.4 Synthesis of(S)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,4-dichlorophenyl)pyrrolidine

Prepare by the method of Example 1.6 using(R)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give thetitle compound.

PREPARATION 44.1

1-(2-(2,2,2-Trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHydriodic acid salt

According to the procedure of Tet. Let., 35, 5997-6000 (1994), combine1-hydroxy-2-tetrahydropyran-2-yloxyethane (J. Chem. Soc. Chem. Commun.,1766 (1990)) (5.0 mmol), 1,1-diethylazodicarboxylate (10 mmol),2,2,2-trifluoroethanol (100 mmol), and tributylphosphine (10 mmol) inbenzene (100 mL). After 6 hours, concentrate in vacuo to give a residue.Chromatograph on silica gel to give 2-tetrahydropyran-2-yloxyethyl2,2,2-trifluorethyl ether.

Combine 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluoroethyl ether (2mmol) and magnesium bromide (6 mmol) in diethyl ether (10 mL). After 24hours, extract with water and then brine. Dry the organic layer overNa₂SO₄, filter, and concentrate in vacuo to give 2-hydroxyethyl2,2,2-trifluoroethyl ether.

Combine 2-hydroxyethyl 2,2,2-trifluoroethyl ether (0.5 mmol) andN,N-diisopropylethylamine (1 mmol) in dichloromethane (20 mL). Cool in aice-bath. Add dropwise, methanesulfonyl chloride (0.6 mmol). After 2hours, extract with 1 M hydrochloric acid solution and 5% sodiumbicarbonate solution. Dry the organic layer over MgSO₄, filter, andconcentrate in vacuo to give 2-methanesulfonyloxyethyl2,2,2-trifluoroethyl ether.

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.5g, 1.6 mmol), tetrahydrofuran (10 mL), and dimethylformamide (10 mL).Add sodium hydride (0.13 g, 3.2 mmol). After 2 hours, add2-methanesulfonyloxyethyl 2,2,2-trifluoroethyl ether (6.0 mmol). After18 hours, heat to 70° C. After 4 hours, cool to ambient temperature andpartition the reaction mixture between water and dichloromethane.Separate the layers, dry the organic layer over Na₂SO₄, filter, andevaporate in vacuo to give1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.5 mmol) and dichloromethane (10 mL). Add hydriodic acid (0.18 mL,57%, 1.0 mmol) and warm to 40° C. After 8 hours, cool to ambienttemperature and evaporate in vacuo to give the title compound.

PREPARATION 44.2

1-(2,2,2-Trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHydriodic acid salt

According to the procedure of Tet. Let., 35, 5997-6000 (1994), combine1-(t-butoxycarbonyl)-4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.0.66 g, 1.81 mmol) and 1,1-diazodicarbonyl dipiperidine (0.5 g, 2mmol) in toluene (20 mL). Add tributylphosphine (0.5 mL, 2 mmol). After10 minutes add 2,2,2-trifluoroethanol (0.7 mL, 10 mmol). Heat to 55° C.After 6 hours, cool to ambient temperature. After 18 hours, evaporate invacuo to give a residue. Chromatograph the residue on silica gel elutingsequentially with hexane, 5% ethyl acetate/hexane, 10% ethylacetate/hexane, 12% ethyl acetate/hexane, and then 30% ethylacetate/hexane to give1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-(t-butoxycarbonyl)-4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.47 g, 1.07 mmol) and methanol (10 mL). Add hydriodic acid (0.7 mL,57%, 9.4 mmol). After 4 hours, evaporate in vacuo to give a residue.Combine the residue and diethyl ether and stir to give a solid. After 18hours, collect the solid by filtration, rinse with diethyl ether, anddry to give the title compound: R_(f)=0.39 (silica gel,dichloromethane/methanol/acetic acid 85/10/5).

EXAMPLE 89

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

89.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 45.1 using1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidineand4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt to give the title compound.

EXAMPLE 90

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-3-methylbut-2-en-1-yl)-1-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

90.1 Synthesis of1-(3,4,5-trimethoxybenzoyl-3-(2-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 35.1 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineand 1-chloro-3-methylbut-2-ene to give the title compound.

EXAMPLE 91

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-allyl-1H-benzimidazol-2-y)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

91.1 Synthesis of1-(3,4,5-trimethoxybenzoyl-3-(2-(4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 35.1 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineand allyl chloride to give the title compound.

PREPARATION 45

2-Methoxy-5-cyanobenzoic acid

Combine methyl ²-methoxy-5-formylbenzoate (5.0 g, 25.9 mmol),hydroxylamine hydrochloride (8.55 g, 133 mmol), and sodium acetate(10.25 g, 125 mmol) in ethanol/water (200 mL, 1/1). Heat: to 50° C.After 1 hour, pour the reaction mixture onto ice to give a solid.Collect the solid byfiltration to give methyl ²-methoxy-5-formylbenzoateoxime: R_(f)=0.76 (silica gel, 9/1 dichloromethane/methanol).

Combine methyl 2-methoxy-5-formylbenzoate oxime (3.5 g, 16.7 mmol) indichloromethane (75 mL) and cool in an ice-bath. Add dropwise thionylchloride (2.0 mL, 27.2 mmol). After 20 minutes, dilute the reactionmixture with dichloromethane and extract with a saturated aqueoussolution of sodium bicarbonate and then brine. Dry the organic layerover MgSO₄, filter, and concentrate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 1/1 ethylacetate/hexane to give methyl 2-methoxy-5-cyanobenzoate

Hydrolyze methyl 2-methoxy-5-cyanobenzoate by the method of Preparation24 using 1.1 equivalents of lithium hydroxide to give the titlecompound.

EXAMPLE 92

1-(2-Methoxy-5-cyanobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

92.1 Synthesis of 1-(2-methoxy-5-cyanobenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4 ]diazepan-1-yl)ethyl-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using 2-methoxy-5-cyanobenzoicacid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give the title compound.

PREPARATION 46

2-Methoxy-5-(1H-tetrazol-5-yl)benzoic acid

Prepare by the method of Example 70.1 using methyl2-methoxy-5-cyanobenzoate to give methyl2-methoxy-5-(1H-tetrazol-5-yl)benzoate: R_(f)=0.21 (silica gel,dichloromethane/methanol 80/20).

Hydrolyze methyl 2-methoxy-5-(1H-tetrazol-5-yl)benzoate by the method ofPreparation 11 to give the title compound.

Alternately, combine 2-methoxy-5-(1H-tetrazol-5-yl)benzoate (1.71 g, 7.3mmol) and an aqueous solution of lithium hydroxide (25 mL, 1 M) inmethanol (40 mL). After 18 hours, heat to reflux. After 1 hour, add anaqueous solution of lithium hydroxide (15 mL, 1 M) and continue thereflux. After 15 hours, cool to ambient temperature, acidify with a 1 Maqueous hydrochloric acid solution and extract four times with ethylacetate and then with dichloromethane. Combine the organic layers, dryover MgSO₄, filter and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially withdichloromethane/methanol 70/30, dichloromethane/methanol 50/50,dichloromethane/methanol 30/70, and then methanol to give the titlecompound.

EXAMPLE 93

1-(2-Methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

93.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 56.1 using2-methoxy-5-(1H-tetrazol-5-yl)benzoic acid and3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaricacid salt) to give, after chromatography on silica gel elutingsequentially with dichloromethane/methanol/concentrated ammoniumhydroxide) 95/5/0.1 dichloromethane/methanol/concentrated ammoniumhydroxide) 80/20/0.2, the title compound: R_(f)=0.81 (silica gel,dichloromethane/methanol/concentrated ammonium hydroxide) 90/10/0.1).

93.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 69.2 using1-(2-methoxy-5-(1H-tetrazol-5-yl)benzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

EXAMPLE 94

1-(2-Methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(1,4)diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethylphenylmethyl)-2-oxopyrrolidine

94.1 Synthesis of1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine

Combine 1-(2-methoxybenzyl)-2-oxopyrrolidine (2.4 g, 11.7 mmol) andtetrahydrofuran (20 mL). Cool to −78° C. using a dry-ice /acetone bath.Add a solution of sec-butyllithium (9.0 mL, 1.3 M in hexane, 11.7 mmol).After 30 minutes, add a solution of 3,5-di(trifluoromethyl)benzylbromide (3.6 g, 11.7 mmol) in tetrahydrofuran (1 mL). After 2 hours, addwater (10 mL). Separate the layers and extract the aqueous layer threetimes with ethyl acetate. Dry the combined organic layers over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 1/1 ethyl acetate/hexane to give thetitle compound: R_(f)=0.53 (silica gel, 1/1 ethyl acetate/hexane).

94.2 Synthesis of1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidine

Combine1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine(4.1 g, 9.5 mmol) and tetrahydrofuran (20 mL). Cool to −78° C. using adry-ice /acetone bath. Add a solution of sec-butyllithium (7.7 mL, 1.3 Min hexane, 9.9 mmol). After 30 minutes, add1-iodo-2-(t-butyldimethylsilyloxy)ethane (2.9 g, 10 mmol) intetrahydrofuran (1 mL). After 2 hours, add water (10 mL). Separate thelayers and extract the aqueous layer three times with ethyl acetate. Drythe combined organic layers over Na₂SO₄, filter, and evaporate in vacuoto give a residue. Chromatograph the residue on silica gel eluting with1/4 ethyl acetate/hexane to give the title compound: R_(f)=0.63 (silicagel, 1/4 ethyl acetate/hexane).

94.3 Synthesis of1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 18.2 using1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-(t-butyldimethylsilyloxy)ethyl)-2-oxopyrrolidineto give the title compound: R_(f)=0.60 (silica gel, ethyl acetate).

94.4 Synthesis of1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine

Prepare by the method of Example 2.5.2 using1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-hydroxyethyl)-2-oxopyrrolidineto give the title compound.

94.5 Synthesis of1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine

Prepare by the method of Example 7.6 using1-(2-methoxybenzyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidineand 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodicacid salt to give the title compound: R_(f)=0.54 (silica gel, 5%methanol/dichloromethane/0.5% concentrated aqeous ammonia).

94.6 Synthesis of1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-2-oxopyrrolidinehydrochloric acid salt

Combine1-(2-methoxybenzyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(3,5-di(trifluoromethyl)phenylmethyl)-2-oxopyrrolidine(0.94 g, 1.25 mmol) and methanol (10 mL). Add a solution of hydrochloricacid in dioxane (0.63 mL, 4 M, 2.5 mmol). After 12 hours, evaporate invacuo to give a residue. Triturate the residue with diethyl ether togive a solid. Repeatedly, decant and add diethyl ether before collectingthe solid by filtration to give the title compound.

PREPARATION 47

4-(1-(N-Methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodicacid salt

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.5g, 1.6 mmol) and dimethylformamide (20 mL). Add sodium hydride (0.08 g,3.2 mmol). After 12 hours, add N-methyl-1-chloroacetamide (0.34 g, 3.14mmol). After 12 hours, add N-methyl-1-chloroacetamide (0.17 g, 1.6mmol). After 12 hours, heat to 70° C. After 4 hours, cool to ambienttemperature and partition the reaction mixture between water (10 mL) anddichloromethane (100 mL). Separate the layers, dry the organic layerover Na₂SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 1.2%methanol/dichloromethane/0.5% saturated aqueous ammonia solution to give1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.24 (silica gel, 1.8% methanol/dichloromethane/0.5% saturatedaqueous ammonia solution).

Combine1-(t-butoxycarbonyl)-4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane(0.18 g, 0.48 mmol) and dichloromethane (10 mL). Add hydriodic acid(0.17 mL, 57%, 0.95 mmol) and warm to 40° C. After 3 hours, cool toambient temperature and evaporate in vacuo to give a residue. Combinethe residue and diethyl ether with stirring to give a solid. Collect thesolid by filtration to give, after drying, the title compound.

EXAMPLE 95

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

95.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 45.1 using1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodicacid salt to give, after chromatography on silica gel eluting with 5%methanol/dichloromethane/0.5% concentrated aqueous ammonia solution, thetitle compound: R_(f)=0.32 (silica gel, 5% methanol/dichloromethane/0.5%concentrated aqueous ammonia solution).

95.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 94.6 using-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 48

4-(1-Allyl-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic acid salt

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane(0.79 g, 2.50 mmol) and sodium hydride (0.13 g, 60%n in oil, 3.254 mmol)in dimethylformlamide (10 mL). After 30 minutes add allyl bromide (0.35mL, 3.25 mmol). Heat to 75° C. After 4 hours, cool the reaction mixture,dilute with dichloromethane, and extract with a saturated aqueous sodiumbicarbonate solution and then brine. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.83 (silica gel, dichloromethane/methanol/concentrated ammoniumhydroxide 90/10/0.1).

Combine1-(t-butoxycarbonyl)-4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane(0.89 g, 2.5 mmol), aqueous hydriodic acid (10 mL, 57%), and ethanol (10mL). Heat to reflux. After 1 hour, cool to ambient temperature, pour thereaction mixture into diethyl ether (250 mL), and stir to give a solid.After 1 hour, collect the solid by filtration, rinse with diethyl ether,and dry in vacuo to give the title compound.

EXAMPLE 96

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

96.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 47.31-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt togive, after purification by chromatography on silica gel elutingsequentially with dichloromethane/methanol/concentrated ammoniumhydroxide 95/5/0.1 and then dichloromethane/methanol/concentratedammonium hydroxide 90/10/0.1, the title compound: R_(f)=0.71 (silicagel, dichloromethane/methanol/concentrated ammonium hydroxide90/10/0.1).

96.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-allyl-1H-benzimidazcol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-allyl-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine,to give the title compound.

EXAMPLE 97

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

97.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 47.31-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt to give, after purification by chromatography onsilica gel eluting sequentially with 2% methanol/dichloromethane, 3%methanol/dichloromethane, 4% methanol/dichloromethane, and then 5%methanol/dichloromethane, the title compound: R_(f)=0.44 (silica gel,10% methanol/dichloromethane).

97.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(2,2,2-triflurorethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 50

1-(Fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic acidsalt

Combine furfuryl alcohol (3.52 mL, 40.8 mmol) and triethylamine (11.4mL, 81.5 mmol) in dichloromethane (70 mL). Cool in an ice-bath. Adddropwise, methanesulfonyl chloride (4.73 mL, 61.2 mmol). After 3 hoursdilute the reaction mixture with dichloromethane, extract with water,and then a saturated aqueous sodium bicarbonate solution. Dry overNa₂SO₄, filter, and evaporate at reduced pressure and a bath temperatureof about 20° C. to give a residue. Distill the residue at about 25° C.and 0.2 mm Hg into a dry-ice trap to obtain 2-(chloromethyl)furan whichis used immediately without further manipulation.

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.7g, 5.37 mmol), tetrahydrofuran (45 mL), and dimethylformamide (5 mL).Cool in an ice-bath. Add sodium hydride (0.32 g, 60%n in oil, 8.06mmol). After 15 minutes, warm to ambient temperature. When gas evolutionceases add 2-(chloromethyl)furan (0.94 g, 8.06 mmol). After 18 hours,cool the reaction mixture, quench by the addition of a saturated aqueousammonium chloride solution. Evaporate to remove most of thetetrahydrofuran, dilute with ethyl acetate, and extract with water, asaturated aqueous sodium bicarbonate solution, and then brine. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 50% ethylacetate/hexane to give1-(t-butoxycarbonyl)-4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.47 (silica gel, ethyl acetate) Elemental Analysis Calculated forC₂₂H₂₈N₄O₃: C, 66.66; H, 7.17; N, 14.04. Found C, 66.65; H, 7.12; N,14.13.

Combine1-(t-butoxycarbonyl)-4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane(0.6 g, 1.5 mmol) and dioxane (10 mL). Add a solution of hydrochloricacid in dioxane (6 mL, 4 M). After 1 hour, add diethyl ether (50 mL) togive a solid. Collect the solid by filtration and dry to give4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepane hydrochloric acidsalt: 219-221° C.

Combine 4-(fur-2-ylmethyl-1H-benzimidazol-2-yl)[1,4]diazepanehydrochloric acid salt (0.56 g, 1.53 mmol) and dichloromethane (150 mL).Extract with a saturated aqueous sodium bicarbonate solution. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give aresidue (about 0.45 g). Combine the residue and methanol (50 mL). Coolin an ice-bath. Add aqueous hydriodic acid (0.11 mL, 57%). After 10minutes, evaporate in vacuo to obtain a residue. Triturate the residuewith diethyl ether to obtain a solid. Collect the solid by filtration,rinse with diethyl ether, and dry to give the title compound.

EXAMPLE 98

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

98.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 47.31-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) and1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt to give, after purification by chromatography on silica gel elutingwith 10% methanol/dichloromethane/0.1% concentrated ammonium hydroxide:R_(f)=0.40 (silica gel, 10% methanol/dichloromethane/0.1% concentratedammonium hydroxide).

98.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(fur-2-ylmethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.73 g, 1.08 mmol) in dichloromethane (15 mL) and methanol (5 mL). Coolin an ice-bath. Add a solution of hydrochloric acid in dioxane (0.54 mL,4 M). Warm to ambient temperature. After 12 hours, add diethyl ether(200 mL) to form a solid. Collect the solid by filtration to give thetitle compound.

PREPARATION 51

2-Methoxy-5-hydroxybenzoic acid

Combine methyl 2,5-dihydroxybenzoate (8.45 g, 50.2 mmol), imidazole (4.1g, 60.3 mmol), and t-butyldimethylsilyl chloride (9.09 g, 60.3 mmol) indichloromethane (100 mL). After 30 minutes, dilute the reaction mixturewith dichloromethane (100 mL) and extract with water. Dry the organiclayer over MgSO₄, filter and evaporate in vacuo to give methyl2-hydroxy-5-(t-butyldimethylsilyloxy)benzoate.

Combine methyl 2-hydroxy-5-(t-butyldimethylsilyloxy)benzoate (14.2 g,50.2 mmol), potassium carbonate (13.88 g, 100.4 mmol), and methyl iodide(20 mL, 321 mmol) in acetone (125 mL). Heat to reflux. After 17 hours,add methyl iodide (10 mL). After 23 hours, cool the reaction mixture toambient temperature and add diethyl ether (600 mL), filter, andevaporate the filtrate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 10% ethyl acetate/hexane to givemethyl 2-methoxy-5-(t-butyldimethylsilyloxy)benzoate. R_(f)=0.39 (silicagel, 5% ethyl acetate/hexane).

Combine methyl 2-methoxy-5-(t-butyldimethylsilyloxy)benzoate (11.1 g.37.4 mmol) and ammonium fluoride (6.94 g, 0.187 mmol) in methanol (150mL). Heat to reflux. After 1 hour, evaporate in vacuo to give a residue.Partition the residue between ethyl acetate and water, separate thelayers, extract the organic layer with water and then brine. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give methyl2-methoxy-5-hydroxybenzoate: mp; 110-112° C. R_(f)=0.27 (silica gel, 5%ethyl acetate/hexane).

Combine methyl 2-methoxy-5-hydroxybenzoate (0.37 g, 2.0 mmol) and a 1 Maqueous sodium hydroxide solution (20 mL, 20 mmol) in methanol (20 mL).After 2 hours, adjust the pH to about 2 using a 1 M aqueous hydrochloricacid solution and extract with dichloromethane. Dry the organic layerover MgSO₄, filter, and evaporate in vacuo to give the title compound.

EXAMPLE 99

1-(2-Methoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4diazepan-1-yl)ethyl)-3-phenylpyrrolidine

99.1 Synthesis of1-(2-methoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt (prepared from(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) (0.53 g, 1.0 mmol), 2-methoxy-5-hydroxybenzoic acid (0.17 g,1.0 mmol), 1-hydroxybenzotriazole hydrate (0.13 g, 1.0 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g, 1.0mmol), and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) indichloromethane (10 mL). After 18 hours, dilute the reaction mixturewith dichloromethane and extract with brine. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give a residue. Chromatographthe residue on silica gel eluting sequentially with 3%methanol/dichloromethane, 5% methanol/dichloromethane, 7%methanol/dichloromethane, and then 10% methanol/dichloromethane to givethe title compound.

99.2 Synthesis of1-(2-methoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-hydroxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 52

1-(2-Methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic acidsalt

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane(2.03 g, 6.41 mmol) and dimethylformamide (50 mL). Cool in an ice-bath.Add sodium hydride (0.28 g, 60%n in oil, 7.0 mmol). After 20 minutes,add 2-chloroethyl methyl ether (0.7 mL, 7.66 mmol). Heat to 85° C. After18 hours, cool to ambient temperature and dilute with dichloromethane,and extract with water, a saturated aqueous sodium bicarbonate solution,and then brine. Dry the organic layer over MgSO₄, filter, and evaporatein vacuo to give a residue. Chromatograph the residue on silica geleluting with dichloromethane/methanol/concentrated ammonium hydroxide95/5/0.05 to give1-(t-butoxycarbonyl)-4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-(t-butoxycarbonyl)-4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(1.69 g, 5.23 mmol), aqueous hydriodic acid (10 mL, 57%), and ethanol(20 mL). Heat to reflux. After 1 hour, cool to ambient temperature andpour the reaction mixture into diethyl ether (350 mL) and stir to give asolid. After 1 hour, collect the solid S by filtration, rinse withdiethyl ether, and dry in vacuo to give the title compound.

EXAMPLE 100

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

100.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.93 g, 1.97 mmol),4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.04 g, 1.97 mmol), and triethylamine (1.5 mL, 10.76 mmol) inacetonitrile (20 mL). Heat to reflux. After 18 hours, cool and partitionthe reaction mixture between brine and dichloromethane. Dry the organiclayer over MgSO₄,filter, and evaporate in vacuo to give residue.Chromatograph the residue on silica gel eluting withdichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05 to givethe title compound: R_(f)=0.49 (silica gel,dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.1).

100.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-methoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 53

1-(But-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic acidsalt

Prepare by the method of Preparation 52 using1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.85 g,2.69 mmol) and crotyl bromide (technical, 0.38 mL, 3.69 mmol) to givethe title compound.

EXAMPLE 101

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

101.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 47.3 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.74 g, 1.41 mmol) and4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.66 g, 1.40 mmol) to give the title compound: R_(f)=0.37 (silicagel, dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.1).

101.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(but-2-en-1-yl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 54

4-(1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic acidsalt

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.5g, 5.03 mmol) and dimethylformamide (30 mL). Add sodium hydride (0.27 g,60%n in oil, 6.5 mmol). After 30 minutes, add 4-fluorobenzyl bromide(1.0 mL, 8.03 mmol). Heat to 80° C. After 2 hours, cool to ambienttemperature and partition the reaction mixture between dichloromethaneand a saturated aqueous sodium bicarbonate solution. Separate the layersand extract the organic layer with brine. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diazepane.

Alternately, combine1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.7 g, 5.37mmol) and dimethylformamide (40 mL). Add sodium hydride (0.23 g, 60%n inoil, 5.75 mmol). After 15 minutes, add 4-fluorobenzyl bromide (0.73 mL,5.86 mmol). After 18 hours, partition the reaction mixture betweendichloromethane and a saturated aqueous sodium bicarbonate solution,Separate the layers and extract the organic layer five times with waterand then brine. Dry the organic layer over Na₂SO₄, filter, and evaporatein vacuo to give1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.42 (silica gel, 50% ethyl acetate/hexane).

Combine1-(t-butoxycarbonyl)-4-(1-(4-fluorobenzyl-1H-benzimidazol-2-yl)[1,4]diazepane(2.50 g, 5.89 mmol), aqueous hydriodic acid (5 mL, 57%), and ethanol (10mL). Heat to reflux. After 1 hour, cool to ambient temperature and pourthe reaction mixture into diethyl ether (450 mL) and stir to give asolid. After 1 hour, collect the solid by filtration, rinse with diethylether, and dry in vacuo to give the title compound: R_(f)=0.16 (silicagel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).

EXAMPLE 102

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

102.1.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 47.3 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(2.2 g, 4.67 mmol) and4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (2.82 g, 4.86 mmol) to give the title compound: R_(f)=0.37 (silicagel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).

102.1.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(2-methoxy-S-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (1.51 g, 3.2 mmol),4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (1.78 g, 3.07 mmol), and triethylamine (2 mL, 14.35 mmol) inacetonitrile (40 mL). Heat to reflux. After 22 hours, cool to ambienttemperature and dilute with dichloromethane, and extract with asaturated aqeous sodium bicarbonate solution and then brine. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting withdichloromethane/methanol/concentrated ammonium hydroxide 95/5/0.05 togive the title compound.

102.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

EXAMPLE 103

1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

103.1 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-fluorobenzoyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 47.3 using1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.72 g, 1.55 mmol.) and4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.88 g, 1.52 mmol) to give the title compound: R_(f)=0.26 (silicagel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).

103.2 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound,

PREPARATION 55

4-(1-(2-(Isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodicacid salt

Combine 2-isopropoxyethanol (1.0 g, 9.6 mmol), N,N-diisopropylethylamine(2.73 g, 21.12 mmol), and dichloromethane (20 mL). Cool in an ice bath.Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol). After 2 hours,dilute the reaction mixture with dichloromethane and extract with 1 Mhydrochloric acid solution, a saturated solution of sodium bicarbonate,and then brine. Dry the organic layer over Na₂SO₄, filter, and evaporatein vacuo to give a residue. Distill the residue to give2-(isopropoxy)ethyl mesylate: bp; 84° C. at 0.1 mm Hg.

Alternately, combine 2-isopropoxyethanol (5.0 g, 48 mmol) anddichloromethane (50 mL). Cool in an ice bath. Add triethylamine (10.7 g,105 mmol). Add dropwise methanesulfonyl chloride (1.43 g, 9.6 mmol).After 2 hours, dilute the reaction mixture with dichloromethane andextract with 1 M hydrochloric acid solution, a saturated aqueoussolution of sodium bicarbonate, and then brine. Dry the organic layerover Na₂SO₄, filter, and evaporate in vacuo to give a residue. Distillthe residue at reduced pressure to give 2-(isopropoxy)ethyl mesylate.

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane(0.54 g, 1.71 mmol), and sodium hydride (0.87 g, 3.48 mmol indimethylformamide (10 mL). After 30 minutes, add 2-(isopropoxy)ethylmesylate (0.51 g, 5.5 mmol). Heat to 80° C. After 2 hours, cool thereaction mixture to ambient temperature and partition betweendichloromethane and a saturated aqueous sodium bicarbonate solution.Separate the layers and extract the organic layer with brine. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.63 g, 1.57 mmol), aqueous hydriodic acid (5 mL, 57%), and ethanol (10mL). Heat to reflux. After 1 hour, cool to ambient temperature and pourthe reaction mixture into diethyl ether (350 mL) and stir to give asolid. After 1 hour, collect the solid by filtration, rinse with diethylether, and dry in vacuo to give the title compound.

EXAMPLE 104

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

104.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 102.1.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.52 g, 1.10 mmol) and4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodicacid salt (0.60 g, 1.08 mmol) to give the title compound: R_(f)=0.28(silica gel, dichloromethane/methanol/concentrated aqueous ammonia90/10/0.1).

104.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 56

4-(1-(2-(t-Butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane

Combine 2-t-butoxyethanol (3.37 g, 28.5 mmol), triethylamine (6 mL, 43mmol), and dichloromethane (150 mL). Cool in an ice bath. Add dropwisemethanesulfonyl chloride (2.9 mL, 37.5 mmol). After 3 days, dilute thereaction mixture with dichloromethane and extract with a saturatedsolution of sodium bicarbonate and then brine. Dry the organic layerover Na₂SO₄, filter, and evaporate in vacuo to give 2-(t-butoxy)ethylmesylate: R_(f)=0.75 (silica gel, 50% ethyl acetate/hexane).

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane(0.56 g, 1.77 mmol), and sodium. hydride (0.088 g, 60% in oil, 2.20mmol) in dimethylformamide (10 mL). Add 2-(t-butoxy)ethyl mesylate (0.40g, 2.04 mmol). Heat to 80° C. After 2 hours, cool to ambient temperatureand partition the reaction mixture between dichloromethane and asaturated aqueous sodium bicarbonate solution. Separate the layers andextract the organic layer with brine. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give1-(t-butoxycarbonyl)-4-1-(2-t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-(t-butoxycarbonyl)-4-(1-(2-t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.89 g, 2.14 mmol), potassium hydroxide (2.46 g, 43.84 mmol), andhydrazine hydrate (2.2. mL, 45.35 mmol) in ethylene glycol (25 mL). Heatto 140° C. After 16 hours, heat to 170° C. After 4 hour, cool to ambienttemperature and partition the reaction mixture between dichloromethaneand a saturated aqueous sodium bicarbonate solution. Separate the layersand extract the organic layer with brine. Dry the organic layer overMgSO₄, filter, and evaporate in vacuo to give the title compound.

EXAMPLE 104

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

104.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.62 g, 1.31 mmol),4-(1-(2-t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (0.41 g, 1.3mmol), sodium iodide (0.42 g, 2.80 mmol), and triethylamine (0.55 mL,3.95 mmol) in acetonitrile (13 mL). Heat to 80° C. After 16 hours, coolto ambient temperature and partition the reaction mixture betweendichloromethane and a saturated aqueous sodium bicarbonate solution.Separate the layers and extract the organic layer with brine. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting sequentiallywith dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05 andthen dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1 togive the title compound: R_(f)=0.86 (silica gel,dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).

104.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(t-butoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-((2-t-butoxy)ethyl))-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine(0.63 g, 0.91 mmol) and dichloromethane (15 mL). Cool in an ice-bath.Add a solution of hydrochloric acid in dioxane (0.5 mL, 4 M, 2.0 mmol).After 10 minutes, pour the reaction mixture into diethyl ether (400 mL)to obtain a solid. Collect the solid by filtration and dry to give thetitle compound.

PREPARATION 57

4-(1-(2-Hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane Hydriodic acidsalt

Combine 2-(t-butyldimethylsilyloxy)ethyl bromide (116.2 g, 486 mmol),and sodium iodide (100 g, 663 mol) in acetone (350 mL) anddimethylformamide (25 mL). Heat to reflux. After 4 hours, cool, filterand evaporate in vacuo to give a residue. Distill the residue to give2-(t-butyldimethylsilyloxy)ethyl iodide: bp; 60° C. at 0.5 mm Hg.

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane(3.06 g, 9.67 mmol) and sodium hydride (0.43 g, 60% in oil, 10.64 mmol)in tetrahydrofuran (60 mL) and dimethylformamide (6 mL). After 2 hours,add 2-(t-butyldimethylsilyloxy)ethyl iodide (2.78 g, 9.67 mmol). After20 hours, heat to reflux. After 4 hours, cool to ambient temperature andadd ice to quench. Evaporate in vacuo to remove most of thetetrahydrofuran. Partition the evaporated reaction mixture between ethylacetate (250 mL) and water (200 mL). Separate the layers and extract theorganic layer with water. Dry the organic layer over MgSO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with ethyl acetate to give1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.58 (silica gel, ethyl acetate).

Alternately, combine1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (1.72 g,5.43 mmol) and sodium hydride (0.36 g, 60% in oil, 8.15 mmol) indimethylformamide (40 mL). After 4 hours, add2-(t-butyldimethylsilyloxy)ethyl iodide (1.56 g, 5.43 mmol). After 72hours, heat to 80° C. After 3 hours, cool to ambient temperature and addice to quench. Partition the reaction mixture between ethyl acetate (250mL) and a saturated aqueous solution of sodium bicarbonate (200 mL).Separate the layers and extract the organic layer with water. Dry theorganic layer over MgSO₄, filter, and evaporate in vacuo to give aresidue. Chromatograph the residue on silica gel eluting with 40% ethylacetate/dichloromethane to give1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.

Combine1-(t-butoxycarbonyl)-4-(1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(4.22 g, 8.88 mmol), and methanol (60 mL). Add ammonium fluoride (1.97g, 53.3 mmol). Heat to reflux. After 2 hours, cool the reaction mixtureand partition between dichloromethane (300 mL) and a saturated aqueoussolution of sodium bicarbonate (200 mL). Separate the layers and extractthe organic layer three times with water and then brine. Dry the organiclayer over MgSO₄, filter, and evaporate in vacuo to give a residue.

Chromatograph the residue on silica gel eluting with ethyl acetate togive1-(t-butoxycarbonyl)-4-(1-(2-hydroethyl)-1H-benzimidazol-2-yl)[1,4]diazepane:R_(f)=0.32 (silica gel, ethyl acetate).

Combine1-(t-butoxycarbonyl)-4-(1-(2-hydroethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.4 g, 1.11 mmol) and methanol (10 mL). Add hydriodic acid (5 mL, 57 %)and heat to reflux. After 2 hours, cool to ambient temperature. Adddiethyl ether (250 mL) to give a solid. Collect the solid by filtrationto give the title compound.

EXAMPLE 106

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

106.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Combine1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt)(0.40 g, 0.85 mmol),4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.44 g, 0.85 mmol) (1.51 g, 3.2 mmol), sodium iodide (0.127 g,0.84 mmol), and triethylamine (0.59 mL, 4.23 mmol) in acetonitrile (20mL). Heat to reflux. After 30 hours, cool to ambient temperature andevaporate in vacuo, and partition the evaporated reaction mixturebetween dichloromethane and a saturated aqueous sodium bicarbonatesolution. Separate the organic layer and extract three times with water.Dry the organic layer over MgSO₄, filter, and evaporate in vacuo to givea residue. Chromatograph the residue on silica gel eluting sequentiallywith dichloromethane, 5% methanol/dichloromethane, 10%methanol/dichloromethane, and then 25% methanol/dichloromethane to givethe title compound.

106.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 98.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound: mp; 172-190° C. (dec).

EXAMPLE 107

1-(2,5-Dimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

107.1 Synthesis of1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)-pyrrolidine

Combine 2,5-dimethoxybenzoic acid (0.71 g, 3.9 mmol) and dichloromethane(30 mL) containing dimethylformamide (0.5 mL). Add oxalyl chloride (0.70mL, 8.55 mmol). After 2 hours, evaporate in vacuo to give a residue,combine the residue and tetrahydrofuran, and add to(−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaricacid salt) (2.33 g, 3.82 mmol) and sodium bicarbonate (2.27 g, 27.02mmol) in tetrahydrofuran/water (20 mL/20 mL). After 2 hours, partitionthe reaction mixture between ethyl acetate and an saturated aqueoussolution of sodium bicarbonate. Separate the layers and and extract theorganic layer with brine, dry over MgSO₄, filter, and evaporate in vacuoto the title compound.

107.2 Synthesis of1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 1.5 using1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine to givethe title compound.

107.3 Synthesis of1-(2,5-dimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 102.1.2 using1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.55 g, 1.27 mmol) and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.71 g, 1.3 mmol) to give, after chromatography on silica geleluting with dichloromethane/methanol/concentrated aqueous ammonia95/5/0.05, the title compound: R_(f)=0.85 (silica gel,dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).

107.4 Synthesis of1-(2,5-dimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2,5-dimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

PREPARATION 58

1-(2-(Trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepaneHydriodic acid salt

According to the procedure of Syn. Comm. 22(17), 2459-2477 (1992),combine 2-benzyloxyethanol (15.21 g, 100 mmol) and tetrahydrofuran. Coolin an ice bath. Add sodium hydride (3.6 g, 150 mmol) and imidazole (0.68g, 10 mmol) After 45 minutes, warm to ambient temperature and add carbondisulfide (15.64 mL, 260 mmol) After 10 minutes add methyl iodide (12.45mL,. 200 mmol) After 20 minutes concentrate in vacuo to give a residue.Chromatograph the residue on silica del eluting with hexane to giveO-(2-benxyloxyethyl)-S-methyl dithiocarbonate.

According to the procedure of Tet Lets. 33(29), 4173-4176 (1992),combine 1,3-dibromo-5,5-hydantoin (17.16 g, 60 mmol) and dichloromethane(100 mL). Cool in a dry-ice/acetone bath. Add a solution ofO-(2-benxyloxyethyl)-S-methyl dithiocarbonate (4.8 g, 20 mmol) indichloromethane (20 mL). Add pyridinium poly(hydrogen fluoride) (40 mL).After 3 hours, warm to about 0° C. After 0.5 hours, slowly pour thereaction mixture into an ice-cooled buffered solution saturated aqueoussodium bicarbonate and aqueous saturated sodium bisulfate and 1 Maqueous sodium hydroxide (pH about 10). Extract three times with ethylacetate. Combine the organic layers, dry over MgSO₄, filter andevaporate in vacuo to give 2-(4-bromobenzyloxy)ethyl trifluoromethylether.

Combine 2-(4-bromobenzyloxy)ethyl trifluoromethyl ether (2.4 g, 8.1mmol), thioanisole (28.5 mL, 243 mmol), and trifluoroacetic acid (30mL). After 24 hours, add potassium bicarbonate to neutralize. Add MgSO₄and chloroform (30 mL). Filter and distill through a short pathdistillation apparatus to give 2-(trifluoroacetoxy) ethyltrifluoromethyl ether containing chloroform which can be used withoutfurther purification.

Combine 2-(trifluoroacetoxy)ethyl trifluoromethyl ether as obtainedabove (containing chloroform), an aqueous solution of sodium hydroxide(405 by weight, 1 mL), and tetrahydrofuran (1 mL). After 30 minutes,filter to give a solution of 2-hydroxyethy trifluoromethyl ether. Addadd molecular sieves to the filtrate. After 30 minutes, filter the abovesolution of 2-hydroxyethy trifluoromethyl ether to remove the molecularsieves. Cool the filtered solution in an ice-bath. AddN,N-diisopropylethylamine (1.4 mL) and methanesulfonyl chloride (0.63mL, 8.1 mmol). After 4 hours, filter the reaction mixture andconcentrate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting sequentially with hexane and then 20% ethylacetate/hexane to give 2-(methanesulfonyloxy)ethyl trifluoromethoxyether: R_(f)=0.21 (silica gel, 20% ethyl acetate/hexane).

Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane(0.31 g, 1 mmol) and dimethylformamide (8 mL). Cool in an ice-bath. Addsodium hydride (0.024 g, 1 mmol). After 2 hours, add2-(methanesulfonyloxy)ethyl trifluoromethoxy ether (0.31 g, 1.5 mmol)and sodium iodide (0.14 g, 1 mmol). Heat to 80° C. After 6 hours, coolto ambient temperature. After 56 hours dilute the reaction mixture withethyl acetate and extract brine. Dry the organic layer over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting sequentially with hexane, 30% ethylacetate/hexane and then 50% ethyl acetate/hexane to give1-(t-butoxycarbonyl)-4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane;R_(f)=0.24 (silica gel, 50% ethyl acetate/hexane).

Combine1-(t-butoxycarbonyl)-4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane(0.18 g, 0.42 mmol) and methanol (5 mL). Add hydriodic acid (2 mL, 57%).After 4 hours, evaporate in vacuo to give the title compound.

EXAMPLE 108

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

108.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 1.61-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt) (0.20 g, 0.42 mmol) and1-(2-trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepanehydriodic acid salt (0.25 g, 0.53 mmol) to give, after purification bychromatography on silica gel eluting sequentially with ethyl acetate,15% methanol/ethyl acetate, and then 10% methanol/dichloromethane, thetitle compound: R_(f)=0.44 (silica gel, 10% methanol/dichloromethane).

108.2 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidinehydrochloric acid salt

Prepare by the method of Example 52.2 using1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidineto give the title compound.

EXAMPLE 109

(−)-1-(3,4,5-Trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

109.1 Resolution of (+)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid salt

Concentrate the mother liquors from the first filtration of Example 33.1to give a residue. Recrystallize three times from methanol/butanone togive the title compound.

109.2 Synthesis of(−)-1-(3,4,5-trimethoxybenzoyl)-(3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine

Prepare by the method of Example 33.2.2 using(+)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine(R,R)-di-p-anisoyltartaric acid to give the title compound.

109.3 Synthesis of1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine

Prepare by the method of Example 2.5.2 using(−)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidineto give the title compound: R_(f)=0.30 (silica gel, ethyl acetate).

109.4 Synthesis of(−)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

Combine1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine(prepared from(−)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine)(0.60 g, 1.24 mmol), sodium iodide (0.195 g, 1.30 mmol), triethylamine(0.864 mL, 6.2 mmol), and4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acidsalt (0.67 g, 1.24 mmol) in acetonitrile (18 mL). Heat to reflux. After24 hours, cool to ambient temperature. After 56 hours, evaporate invacuo to obtain a residue. Partition the residue between dichloromethaneand a saturated aqueous sodium bicarbonate solution. Separate theorganic layer, extract with water and then brine, dry over Na₂SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 10% methanol/dichloromethane to givethe title compound.

109.5 Synthesis of(−)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidinehydrochloric acid salt

Prepare by the method of Example 33.5 using(−)-1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidineto give the title compound.

EXAMPLE 110

1-(2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-1-(2-(1H-imidaol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

110.1 Synthesis of1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-(2-(4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine

Prepare by the method of Example 66.1 using1-(2-methoxy-5-(1h-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine(0.40 g, 0.84 mmol) and4-(1-(2-(1H-imidazol-1-yl)ethyl)-1H-benzimidazol-2-yl)(1,4]diazepanehydriodic acid salt (0.48 g, 0.84 mmol) to give the title compound:R_(f)=0.18 (silica gel, 5% methanol/dichloromethane/0.5% concentratedaqueous ammonia).

In another aspect of the present invention, there are disclosed othernovel substituted 4-(1H-benzimidazol-2-yl)[1,4]diazepane derivatives ofthe formula:

wherein

m is 2 or 3;

A is 1 or 2;

G is —C(O)—, —C(O)—CH₂—, or —SO₂—;

R₃₀ is selected from the group consisting of:

—C₅-C₈ alkyl, —(CH₂)_(p)CF₃, vinyl,

wherein

p is an integer from 1 to 4;

B is an integer from 1 to 4;

D is an integer from 1 to 4;

s is an integer from 1 to 4; and

R₃₄ is C₁-C₄ alkyl;

R₃₁ and R₃₂ are the same or different and are independently selectedfrom hydrogen or C₁-C₄ alkoxy; and

R₃₃ is selected from the group consisting of:

hydrogen, C₁-C₄ alkoxy,

wherein

E is an integer from 2 to 4.

Examples of compounds encompassed by this aspect of the presentinvention include the following. It is understood that the examplesencompass the specific stereoisomers and diastereomers, whereapplicable, of the compounds and mixtures thereof. This list is meant tobe representative only and is not intended to limit the scope of theinvention in any way:

1-[(R)-3-(2-{4-[1-(2-Cyclopropylmethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone

1-((R)-3-{2-[4-(1-Cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-{(R)-3-[2-(4-{1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepan-1-yl)-ethyl]-3-phenyl-pyrrolidin-1-yl}-methanone

1-{(R)-3-[2-(4-{1-[2-(2-Methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepan-1-yl)-ethyl]-3-phenyl-pyrrolidin-1-yl}-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-(2-{4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanone

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanone

Methanesulfonic acid3-{1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phenyl ester

1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(2-methoxy-ethoxy)-phenyl]-methanone

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-{2-[4-(1-pentyl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-methanone

1-(3-{1-[(R)-3-(2-{4-1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phenoxy)-propan-2-one

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanone

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanone

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-{2-[4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-pyrrolidin-1-yl)-methanone

Methanesulfonic acid4-{1-[(R)-3-(2-{4-[1-2(ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-2,6-dimethoxy-phenylester hydrochloride

1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-phenyl]-methanone

1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-phenyl]-methanone

2-(4-{2-[(R)-1-(2,5-Dimethoxy-benzenesulfonyl)-3-phenyl-pyrrolidin-3-yl]-ethyl}-[1,4]diazepan-1-yl)-1-(2-ethoxy-ethyl)-1H-benzoimidazolehydrochloride

1-[3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-azetidin-1-yl]-2-(3,4,5-trimethoxy-phenyl)-ethanonehydrochloride

EXAMPLE 111

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-(2-{4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl-methanone

Treat a solution of1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.89 g, 2.77mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride(0.15 g, 3.05 mmol, 49% dispersion in oil ) at room temperature. After15 minutes, add slowly a solution of 4-chloromethyl-2-methylthiazolehydrochloride (0.56 g, 3.05 mmol, Lancaster Synthesis) anddimethylformamide (10 mL). After stirring 12 hours at room temperature,add water (10 mL) slowly and extract with dichloromethane.(150 mL). Washthe organic phase with water (3×10 mL), dry (Na₂SO₄) the organic layer,filter, concentrate the filtrate to remove the solvent and purify theresidue by chromatography on silica gel eluting with 5% methanol indichloromethane. Concentrate the desired fractions to afford 1.02 g of4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester.

Hydrolyze4-[1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.59 g, 1.38 mmol) by refluxing with hydriodicacid (57%, 3.04 mmol) in methanol (10 mL) for 10 hours. Concentrate toremove the methanol, add ether (70 mL) and allow the resultant slurry tostand for 1 hour. Decant the supernatant and dry the solid residue invacuo at 60° C. to provide 0.78 g of2-[1,4]diazepan-1-yl-1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazoledihydroiodide.

Add diisopropylethylamine (0.69 g, 5.32 mmol) to a mixture of2-[1,4]diazepan-1-yl-1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazoledihydroiodide (0.78 g, 1.33 mmol), methanesulfonic acid2-{(S)-1-[-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.63 g, 1.33 mmol, Example 47.2) and acetonitrile (20 mL). Refluxfor 12 hours. Cool and pour the mixture into a separatory funnel, dilutewith dichloromethane (100 mL), wash twice with water (10 mL portions),dry (Na₂SO₄) the organic phase, filter and evaporate. Purify the residueby silica gel chromatography eluting with 5% methanol in dichloromethaneto afford 0.45 g of the title compound, Rf =0.41 (silica gel, 10%methanol in dichloromethane). The material may be converted to thedihydrochloride salt by methods well known in the art.

EXAMPLE 112

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-{2-[4-(1-pentyl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-methanone

Treat a solution of1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.59 g, 1.86mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride(0.11 g, 2.75 mmol, 60% dispersion in oil) at room temperature. After 15minutes, add pentyl bromide (0.34 mL, 2.74 mmol, Aldrich ChemicalCompany) and heat overnight at 80° C. Cool the reaction and dilute withdichloromethane (150 mL). Extract the organic phase with brine, dry(Na₂SO₄), filter and concentrate the filtrate to afford4-(1-pentyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acidtert-butyl ester (0.71 g, R_(f)=0.87, silica gel, 95:5:0.5dichloromethane:methanol:ammonium hydroxide).

Hydrolyze 4-(1-pentyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.70 g, 1.81 mmol) by refluxing an ethanolsolution of the compound with hydroiodic acid (57%, 5 mL) as describedin Example 111 to provide2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazole dihydroiodide (0.85 g).

Heat a mixture of 2-[1,4]diazepan-1-yl-1-pentyl-1H-benzoimidazoledihydroiodide (0.83 g, 1.53 mmol), methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.713 g, 1.51 mmol, example 47.2), diisopropylethylamine (1 mL,5.74 mmol) and acetonitrile (15 mL) at 90° C. for 72 hours. Concentrateto dryness and dissolve the residue in dichloromethane. Wash thedichloromethane phase with NaHCO₃ (10%, 10 mL) and brine (four 10 mLportions), dry (Na₂SO₄) the organic phase, filter and evaporate. Purifythe residue by silica gel chromatography (3.5×35 cm) eluting with95:5:0.05 dichloromethane:methanol:30% ammonium hydroxide solution.Concentrate the desired fractions to afford 0.19 g of the titlecompound, R_(f)=0.80 (silica gel, 90:10:0.1 dichloromethane:methanol:30%ammonium hydroxide solution). The product may be converted to thedihydrochloride by methods as are well known in the art.

EXAMPLE 113

1-((R)-3-{2-[4-(1-Cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone

Treat a solution of1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.50 g, 1.58mmol, Preparation 9) and dimethylformamide (10 mL) with sodium hydride(0.083 g, 2.08 mmol, 60% dispersion in oil) at room temperature. After15 minutes, add (bromomethyl)cyclopropane (0.21 mL, 2.17 mmol, AldrichChemical Company) and heat two hours at 80° C. Cool the reaction andpartition between dichloromethane (150 mL) and NaHCO₃ solution (40 mL).Wash the organic phase with brine (40 mL), dry (MgSO₄), filter andconcentrate the filtrate to afford4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.71 g, R_(f)=0.87, silica gel, 95:5:0.5dichloromethane:methanol:ammonium hydroxide).

Hydrolyze4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.70 g, 1.81 mmol) by refluxing an ethanol (10mL) solution of the compound with hydroiodic acid (57%, 5 mL) for 1 houras described in Example 111 to provide1-cyclopropylmethyl-2-[1,4]diazepan-1-yl-1H-benzoimidazole dihydroiodide(0.85 g)

Reflux a mixture of1-cyclopropylmethyl-2-[1,4]diazepan-1-yl-1H-benzoimidazole dihydroiodide(0.60 g, 1.14 mmol), methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.53 g, 1.12 mmol, example 47.2), triethylamine (0.65 mL, 4.66mmol) and acetonitrile (10 mL) for 8 hours. Cool and dilute withdichloromethane (150 mL), wash the organic phase with NaHCO₃ (30 mL) andsaturated brine solution (30 mL), dry (MgSO₄) the organic phase, filterand evaporate. Purify the residue by silica gel chromatography (4×41 cm)eluting with dichloromethane:methanol:30% ammonium hydroxide (95:5:0.05}to afford 0.47 g of the title compound, R_(f)=0.32 (silica gel,dichloromethane:methanol:30% ammonium hydroxide solution. The compoundmay be converted to the dihydrochloride salt by methods well known inthe art.

EXAMPLE 114

1-{(R)-3-[2-(4-{1-[2-(2-Methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepan-1-yl)-ethyl]-3-phenyl-pyrrolidin-1-yl}-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone

Treat a solution of1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (preparation9, 0.50 g, 1.58 mmol) and dimethylformamide (10 mL) with sodium hydride(0.083 g, 2.08 mmol, 60% dispersion in oil) at room temperature. After30 minutes, add 1-bromo-2-(2-methoxyethoxy)ethane (0.34 g, 1.88 mmol,Aldrich Chemical Company) and heat two hours at 70° C. Cool thereaction, add water (10 mL) and extract with dichloromethane (100 mL).Wash the organic phase with water, dry (Na₂SO₄), filter and concentratethe filtrate to afford4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.62 g).

Hydrolyze4-{1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.73 g, 1.73 mmol) with hydroiodic acid (57%, 5mL) for 1 hour as described in Example 113 to provide2-[1,4]diazepan-1-yl-1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazoledihydroiodide (0.73 g).

Heat a mixture of2-[1,4]diazepan-1-yl-1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazoledihydroiodide (0.71 g, 1.24 mmol), methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.60 g, 1.27 mmol, example 47.2) and acetonitrile (10 mL),triethylamine (1.2 mL, 8.61 mmol) and acetonitrile (15 mL) at 85° C. for18 hours. Quench the reaction and purify the crude product as describedin Example 113 to afford 0.51 g of the title compound, R_(f)=0.40(silica gel, dichloromethane:methanol:30% ammonium hydroxide,90:10:0.1). The compound may be converted to the dihydrochloride salt bymethods well known in the art.

EXAMPLE 115

1-[(R)-3-(2-{4-[1-(2-Cyclopropylmethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanone

Treat a dry ice/acetone chilled mixture of1-(t-butoxycarbonyl)-4-(1-2-hydroxyethyl)1H-benzimidazol-2-yl)-[1,4]diazepane(0.50 g, 1.39 mmol, Preparation 8) and sodium hydride (0.058 g, 1.46mmol, 60% in oil dispersion) under argon via syringe with anhydroustetrahydrofuran (9 mL). Allow the mixture to stir at 0° C. for 1.5hours, then add (bromomethyl)cyclopropane (1.1 equivalents, AldrichChemical Company) dropwise. Stir the reaction mixture at roomtemperature for 20 hours and then reflux under argon for 1.5 hours. Thinlayer chromatographic analysis (silica gel, ethyl acetate) indicates thepresence of starting material. Treat the reaction mixture with sodiumhydride (0.03 g). Stir 18 hours, quench the reaction with ice, stir 30minutes and concentrate in vacuo. Dissolve the residue indichloromethane, wash with NaHCO₃ solution (100 mL) and water (3×150mL), wash with saturated brine (100 mL), dry the organic phase (MgSO₄)and concentrate. Purify the residue by column chromatography on silicagel (6×45 mm) eluting the column with 60% ethyl acetate indichloromethane to give4-[1-(2-cyclopropylmethoxyethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.32 g; R_(f)=0.55, silica gel, ethyl acetate).

Treat a solution of4-[1-(2-cyclopropylmethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.32 g, 0.76 mmol) and dioxane (4 mL) with 4N HClin dioxane (2.3 mL, 12 equivalents) with stirring. After 90 minutesconcentrate to remove the solvent, add 2.5 mL, of dichloromethane andthen add ether dropwise with stirring. Repeat the process ofconcentration, dissolving in dichloromethane (2 mL) and treating thesolution with ether and allowing the mixture to stir overnight until asuspension of yellow crystalline material is obtained. Collect theprpeipitate by filtration under argon, wash with ether and dry in vacuoovernight to give1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazoledihydrochloride (0.22 g). Treat a slurry of1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazoledihydrochloride (0.16 g, 0.42 mmol) and dichloromethane (150 mL) withsaturated NaHCO₃ solution. Extract the aqueous phase once withdichloromethane (100 mL). Wash the combined dichloromethane phases withwater (3×200 mL) and saturated brine (100 mL), dry (MgSO₄) the organicphase, filter and concentrate to afford a1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole asa yellow oil (0.10 g).

Heat at 81° C. a mixture of1-(2-cyclopropylmethoxy-ethyl)-2-[1,4]diazepan-1-yl-1H-benzoimidazole(0.10 g, 0.33 mmol) and methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.60 g, 1.27 mmol, example 47.2), triethylamine (0.136 mL, 3equivalents), sodium iodide (0.097 g, 2 equivalents) and acetonitrile(8.1 mL) under argon for 30 hours. Quench the reaction as described inExample 113. Purify the crude material by column chromatography (silicagel, 4.5 cm×15 cm, using step gradient elution with 0%, 5% and 10%methanol in dichloromethane. Concentrate the appropriate fractions toafford 0.16 g of the title compound, R_(f)=0.33 (silica gel, 10%methanol in dichloromethane). The compound may be converted to thedihydrochloride salt, m.p. 135-155° C. (dec.), by methods well known inthe art.

EXAMPLE 116

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanone

Treat a stirred solution of pyrazole (0.22 g, 3.18 mmol, AldrichChemical Company) and dimethylformamide (5 mL) at room temperatureportionwise with sodium hydride (0.15 g, 3.18 mmol). After 30 minutes,slowly add a solution of1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane(0.93 g, 2.12 mmol, Preparation 28) and dimethylformamide, and then heatat 75° C. for 12 hours. Cool, add dichloromethane (100 mL) and wash withwater (2×20 mL). Dry (Na₂SO₄) the organic phase, filter and concentrate.Dry the residue under high vacuum at 100° C. to remove residualdimethylformamide. Purify the residue by radial chromatography (silicagel, ethyl acetate:hexane, 1:1) to afford4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.71 g), R_(f)=0.44 (silica gel, ethyl acetate).

Reflux4-[1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.71 g, 1.73 mmol) in methanol (15 mL) withhydroiodic acid (57%, 0.5 mL) for 12 hours. Cool, add ether (80 mL) toafford a suspension and stir the suspension for one hour. Collect thesolid by filtration and dry to provide2-[1,4]diazepan-1-yl-1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazoledihydroiodide (0.81 g).

Reflux a mixture of2-[1,4]diazepan-1-yl-1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazoledihydroiodide (0.48 g, 0.84 mmol), methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.40 g, 0.84 mmol, example 47.2), diisopropylethylamine (0.44 g,3.37 mmol) and acetonitrile (20 mL) for 12 hours. Cool and dilute withdichloromethane (150 mL), wash the organic phase with water (2×10 mL),dry (MgSO₄) the organic phase, filter and evaporate. Purify the residueby silica gel chromatography eluting with 0.5% methanol indichloromethane to afford 0.29 g of the title compound, R_(f)=0.18(silica gel, 0.5% methanol in dichloromethane). The compound may beconverted to the dihydrochloride salt by methods well known in the art.

EXAMPLE 117

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-{(R)-3-[2-(4-{1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazol-2-yl-[1,4]diazepan-1-yl)-ethyl]-3-phenyl-pyrrolidin-1-yl}-methanone

Treat a stirred solution of 5-methyltetrazole (0.38 g, 4.52 mmol,obtained from TCI US) and dimethylformamide (7 mL) at 0° C. portionwisewith sodium hydride (0.19 g, 4.75 mmol, 60% dispersion in oil). Allow towarm to room temperature over one hour and add a solution of1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane(0.1.33 g, 3.03 mmol, Preparation 28) and dimethylformamide (7 mL). Heatat 100° C. for 6 hours. Cool, add ethyl acetate (50 mL) and wash withsaturated NaHCO₃ (3×25 mL) and brine (3×50 mL). Dry (MgSO₄) the organicphase, filter and concentrate in vacuo. Purify the residue bychromatography (silica gel, 3.5×50 cm) eluting with ethyl acetate:hexane(1:1) to afford4-{1-[2-(5-methyl-tetrazol-1-yl}-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.45 g), R_(f)=0.21 (silica gel,methanol:dichloromethane, 1:1).

Reflux4-{1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazol-2-yl}-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.42 g, 0.98 mmol) in ethanol (15 mL) with 57%hydroiodic acid (5 mL) for one hour. Cool, treat with sodium hydroxidesolution (final pH 13) and extract with dichloromethane (10×50 mL). Drythe combined organic phases (Na₂SO₄), filter and concentrate thefiltrate in vacuo to afford2-[1,4]diazepan-1-yl-1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazole(0.27 g), R_(f)=0.60 (silica gel, dichloromethane:methanol:ammoniumhydroxide solution, 80:20:0.2).

Reflux a mixture of2-[1,4]diazepan-1-yl-1-[2-(5-methyl-tetrazol-1-yl)-ethyl]-1H-benzoimidazole(0.27 g, 0.83 mmol), methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.40 g, 0.84 mmol, example 47.2), diisopropylethylamine (1.0 mL,1.27 mmol), potassium iodide (0.21 g, 1.27 mmol) and acetonitrile (20mL) overnight. Concentrate in vacuo to remove the solvent and purify theresidue by silica gel chromatography (3.5×30 cm) eluting withdichloromethane:methanol:30% ammonium hydroxide solution, (95:5:0.5).Combine and concentrate the appropriate fractions to afford 0.19 g ofthe title compound, R_(f)=0.36 (silica gel, dichloromethane:methanol:30%ammonium hydroxide solution, 90:10:0.1). The compound may be convertedto the dihydrochloride salt by methods well known in the art.

EXAMPLE 118

Methanesulfonic acid3-{1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phenylester

Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate (Danishefsky etal., J. Med. Chem. 1979, 101, 7001-7008, 0.37 g, 2 mmol) and 1N NaOH fortwo hours at room temperature. Acidify with 1N HCl and extract withdichloromethane. Dry (MgSO₄) the organic phase, filter and concentratethe filtrate in vacuo. Vacuum dry the residue at room temperatureovernight to afford 4-hydroxy-2-methoxybenzoic acid (0.34 g).

Stir a mixture of1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazoledihydrochloride (0.53 g, 1 mmol, Preparation 12.1, named as3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine),4-hydroxy-2-methoxybenzoic acid (0.34 g),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.19 g, 1 mmol, AldrichChemical Company), 1-hydroxybenzotriazole hydrate (0.14 g, 1 mmol,Aldrich Chemical Company), diisopropyoethylamine (3.4 mL) anddichloromethane (10 mL) overnight at room temperature. Dilute thereaction mixture with dichloromethane, wash with saturated brine, dry(MgSO₄) the organic phase, filter and concentrate the filtrate in vacuo.Purify the residue by column chromatography on silica gel elutingsequentially with ethyl acetate, 3% methanol in dichloromethane and 10%methanol in dichloromethane. Concentrate the appropriate fractions toafford1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(5-hydroxy-2-methoxy-phenyl)-methanone(0.19 g), R_(f)=0.38 (silica gel, 10% methanol in dichloromethane).

Treat a stirred solution of1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(5-hydroxy-2-methoxy-phenyl)-methanone(0.25 g, 0.22 mmol) and dichloromethane (5 mL) at 0° C. withdiisopropylethylamine (0.14 mL, 0.84 mmol) and methane sulfonyl chloride(0.04 mL, 0.5 mmol). Stir the reaction mixture at 0° C. for two hours,dilute with dichloromethane and wash with water. Dry (MgSO₄) the organicphase, filter and concentrate the filtrate in vacuo. Purify the productby column chromatography (silica gel, elute sequentially with 3%methanol in dichloromethane then with 5% methanol in dichloromethane)and concentrate the appropriate fractions to afford 0.19 g of the titlecompound, R_(f)=0.28 (silica gel, 5% methanol in dichloromethane). Thecompound may be converted to the dihydrochloride salt by methods swellknown in the art.

EXAMPLE 119

1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(2-methoxy-ethoxy)-phenyl]-methanone

Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate (Danishefsky etal., J. Med. Chem. 1979, 101, 7001-7008, 0.73 g, 4 mmol), 2-chloroethylmethy ether (1 mL, 12 mmol, Aldrich Chemical Company), potassiumcarbonate (0.55 g, 4.8 mmol) and dimethylformamide (20 mL) at 50° C.overnight. Cool to room temperature, add 2-chloroethyl methy ether (1mL) and potassium carbonate (1.36 g), and heat with stirring at 70° C.for six hours. Cool and dilute with ethyl acetate, wash with saturatedbrine, dry (Na₂SO₄) the organic phase, filter and concentrate thefiltrate in vacuo. Vacuum dry the residue overnight at room temperatureto afford 0.94 g of 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid methylester.

Stir a mixture of 2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid methylester (0.87 g, 3.6 mmol), methanol (20 mL) and 1N NaOH solution (20 mL)for two hours at room temperature. Acidify the reaction with 1N HCl andextract with dichloromethane. Dry (MgSO₄) the organic phase, filter andconcentrate the filtrate in vacuo. Vacuum dry the residue at roomtemperature over 48 hours to afford 0.82 g of2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid as an oil, R_(f)=0.84(silica gel, dichloromethane:methanol:acetic acid, 85:10:5).

Stir a mixture of1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazoledihydrochloride (0.32 g, 0.6 mmol, Preparation 12.1),2-methoxy-5-(2-methoxy-ethoxy)-benzoic acid (0.16 g, 0.72 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.72 mmol),1-hydroxybenzotriazole hydrate (0.097 g, 0.72 mmol),diisopropyoethylamine (0.2 mL, 1.2 mmol) and dichloromethane (20 mL)overnight at room temperature. Dilute the reaction mixture withdichloromethane, wash with saturated brine, dry (MgSO₄) the organicphase, filter and concentrate the filtrate in vacuo. Purify the residueby column chromatography on silica gel eluting sequentially with ethylacetate, 5% methanol in dichloromethane and 10% methanol indichloromethane. Concentrate the appropriate fractions to afford 0.32 gof the title compound, R_(f)=0.46 (silica gel, 10% methanol indichloromethane). The compound may be converted to the dihydrochloridesalt by methods well known in the art.

EXAMPLE 120

1-(3-{1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-methanoyl}-4-methoxy-phenoxy)-propan-2-one

Stir a mixture of methyl 4-hydroxy-2-methoxybenzoate (Danishefsky etal., J. Med. Chem. 1979, 101, 7001-7008, 0.54 g, 3 mmol), chloroacetone(6 mmol, Aldrich Chemical Company), potassium carbonate (9 mmol) anddimethylformamide at 50° C. overnight. Cool the reaction to roomtemperature, dilute with ethyl acetate, wash with saturated NaHCO₃solution and saturated brine. Dry (MgSO₄) the organic phase, filter andconcentrate the filtrate in vacuo. Purify the residue by columnchromatography (silica gel, step gradient elution with 10% ethyl acetatein hexane to 30% ethyl acetate in hexane) and concentrate theappropriate fractions to afford 0.73 g of2-methoxy-5-(2-oxo-propoxy)-benzoic acid methyl ester.

Stir a mixture of 2-methoxy-5-(2-oxo-propoxy)-benzoic acid methyl ester(0.49 g, 2.1 mmol), methanol (20 mL) and 1N NaOH (20 mL, 20 mmol) fortwo hours at room temperatue. Acidify the reaction with 1N HCl (to pH 2)and extract with dichloromethane. Dry (MgSO₄) the organic phase, filterand concentrate the filtrate in vacuo. Purify the residue by columnchromatography (silica gel, step gradient elution with 3% methanol indichloromethane to 10% methanol in dichloromethane and concentrate theappropriate fractions to afford 0.38 g of2-methoxy-5-(2-oxo-propoxy)-benzoic acid, R_(f)=0.82 (silica gel,dichloromethane:methanol:acetic acid, 85:10:5).

Stir a mixture of1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazoledihydrochloride (0.33 g, 0.61 mmol, Preparation 12.1),2-methoxy-5-(2-oxo-propoxy)-benzoic acid (0.14 g, 0.61 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.14 g, 0.73 mmol),1-hydroxybenzotriazole hydrate (0.099 g, 0.73 mmol),diisopropylethylamine (0.25 mL, 1.2 mmol) and dichloromethane (10 mL)overnight at room temperature. Dilute the reaction mixture withdichloromethane, wash with saturated brine, dry (MgSO₄) the organicphase, filter and concentrate the filtrate in vacuo. Purify the residueby column chromatography on silica gel eluting sequentially with ethylacetate, 3% methanol in dichloromethane and 5% methanol indichloromethane. Concentrate the appropriate fractions to afford 0.35 gof the title compound, R_(f)=0.48 (silica gel, 10% methanol indichloromethane). The compound may be converted to the dihydrochloridesalt by methods well known in the art.

EXAMPLE 121

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanone

Treat a stirred solution of1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (1.50 g, 4.74mmol, Preparation 9), tetrahydrofuran (45 mL) and dimethylformamide (5mL) at 0° C. with sodium hydride (0.228 g, 5.69 mmol, 60% oildispersion) under an argon atmosphere. Stir at room temperatue for 30minutes, cool to 0° C. and treat with 1-iodo-4,4,4-trifluorobutane (1.35g, 5.69 mmol, Lancaster Synthesis). Allow to warm slowly to roomtemperature and stir overnight at room temperature. Cool to 5° C.,quench by addition of ice and saturated ammonium chloride solution (5mL) and concentrate in vacuo to remove the tetrahydrofuran. Dissolve theresidue in ethyl acetate (150 mL), wash the organic phase with water(3×40 mL), dry (Na₂SO₄), filter and concentrate to afford a yellow oil.Purify by flash chromatography (silica gel, 7×40 cm) eluting with 60%ethyl acetate in hexane. Concentrate the appropriate fractions in vacuoand dry the residue (1.2 Torr, 50° C., 2 hours) to afford 1.93 g of4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester as an oil, R_(f)=0.40 (silica gel, ethyl acetate).

Treat a solution of4-[1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (1.80 g, 4.22 mmol) and methanol (15 mL) at 0° C.with 57% hydroiodic acid (3.79 g, 16.9 mmol). Stir at room temperaturefor 30 minutes, heat to 50° C. for two hours and then stir at roomtemperature overnight. Thin layer analysis (silica gel, ethyl acetate)indicates the presence of starting material. Add 57% hydroiodic acid(1.12 mL) and heat at 50° C. for two hours. Concentrate in vacuo toremove the methanol, dissolve the residue in methanol (10 mL) and addether (total of 200 mL) to afford a white tacky precipitate. Decant thesupernatant, add ether (200 mL) and stir to afford a cream coloredsolid. Collect the solid by vacuum filtration under nitrogen and dry invacuo at 82° C. (0.2 Torr) overnight to afford 2.25 g of2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazoledihydroiodide, m.p. 206-208° C. Elemental Analysis: Calculated forC₁₆H₂₁F₃N₄.2HI: 33.01%C, 3.98%H, 9.62%N; Found 33.15%C, 3.87%H, 9.41%N.

Reflux a solution of2-[1,4]diazepan-1-yl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazoledihydroiodide (0.65 g, 1.12 immol), methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.50 g, 1.06 mmol, example 47.2), triethylamine (3.58 mmol) andacetonitrile (15 mL) for 20 hours. Cool and concentrate in vacuo. Dilutewith dichloromethane (150 mL), wash the organic phase with NaHCO₃solution (3×30 mL), dry (Na₂SO₄) the organic phase, filter andevaporate. Purify the residue by flash chromatography (silica gel, 7×15cm) eluting with 10% methanol/0.1% ammonium hydroxide solution indichloromethane and concentrate the appropriate fractions to afford 0.79g of the title compound as a cream colored foam, R_(f)=0.46 (silica gel,1.0% methanol/0.1% ammonium hydroxide solution in dichloromethane). Thecompound may be converted to the dihydrochloride salt by methods wellknown in the art.

EXAMPLE 122

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-[(R)-3-phenyl-3-(2-{4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-pyrrolidin-1-yl]-methanone

Treat a solution of 2,2,2-trifluoroethanol (170 mmol), pyridine (13.5mL, 170 mmol) nd dichloromethane at 0° C. dropwise over 45 minutes witha solution of triflic anhydride (196 mmol) and dichloromethane (170 mL).Quench the reaction with water, wash the organic hase with water, dry(MgSO₄), filter and concentrate by fractional distillation to afford1,1,1-trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester.

Add to a suspension of sodium hydrdide (0.029 g, 1.21 mmol) in anhydrousdimethylformamide (5 mL) a suspension of1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan (0.38 g, 1.2mmol, Preparation 9) in anhydrous dimethylformamide (7 mL). Stir for 3hours at room temperature and add a large excess of1,1,1-trifluoro-methanesulfonic acid 2,2,2-trifluoro-ethyl ester. Stirovernight at room temperature, quench the reaction with water, wash theorganic phase with water, dry (MgSO₄), filter and concentrate in vacuoto afford4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester. Repeat this preparation using 2.88 mmol of1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepan. Combine theproduct from both reactions and purify by column chromatography onsilica gel eluting with 30% ethyl acetate in hexane and concentrate theappropriate fractions to afford 0.48 g of4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester.

Stir a solution of4-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester (0.43 g, 1.07 mmol), methanol (10 mL) and 57%hydroiodic acid overnight at room temperature, and then heat for twohours at 50° C. Cool, add 57% hydroiodic acid (1 mL) and heat for twohours. Concentrate in vacuo to remove the solvents, dilute the residuewith methanol (150 mL), concentrate in vacuo, and triturate the residualoil with ether (300 mL) to afford a tan solid. Stir the mixture for onehour, collect the solid by vacuum filtration under nitrogen, and dry invacuo (0.2 Torr) at 82° C. to afford 0.54 g of2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazoledihydroiodide, m.p. >225° C. Elemental Analysis: Calculated forC₁₄H₁₉F₃N₄.2HI: 30.35%C, 3.46%H, 10.11%N; Found 30.46%C, 3.33%H, 9.79%N.

Reflux a stirred solution of2-[1,4]diazepan-1-yl-1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazoledihydroiodide (0.44 g, 0.79 mmol), methanesulfonic acid2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethylester (0.38 g, 0.79 mmol, example 47.2), triethylamine (2.54 mmol) andacetonitrile (11 mL) under argon for 20 hours. Cool and concentrate invacuo. Dilute with dichloromethane (100 mL), wash the organic phase withNaHCO₃ solution (2×20 mL), dry (Na₂SO₄) the organic phase, filter andevaporate in vacuo. Purify the residue by flash chromatography (silicagel, 7×15 cm) eluting with 10% methanol/0.1% ammonium hydroxide solutionin dichloromethane, concentrate the appropriate fractions, and dry theresultant material in vacuo (0.2 Torr) for 2 hours to afford 0.41 g ofthe title compound as a beige colored foam, R_(f)=0.39 (silica gel, 10%methanol/0.1% ammonium hydroxide solution in dichloromethane). Thecompound may be converted to the dihydrochloride salt by methods wellknown in the art.

EXAMPLE 123

1-(2-Methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-{2-[4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepan-1-yl]-ethyl}-pyrrolidin-1-yl)-methanone

4-(1-Vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acidtert-butyl ester is the major product obtained from an alternativesynthesis of1-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane(Preparation 44.2). Treat a stirred solution of1-(t-butoxycarbonyl)-4-(1-(2-methanesulfonyloxyethyl)-1H-benzimidazol-2-yl)-[1,4]diazepane(1.21 g, 2.77 mmol, Preparation 9), 2,2,2-trifluoroethanol (2.75 g, 27.4numol, Aldrich Chemical Company), anhydrous tetrahydrofuran (20 mL) anddimethylformamide (2 mL) at 0-5° C. with sodium hydride (0.44 g, 11mmol, 60% oil dispersion) under an argon atmosphere. Stir overnight atroom temperature, heat at 50° C. for four hours, and stir at roomtemperature for two hours. Cool to 0° C., quench by addition ofsaturated ammonium chloride solution (5 mL) and concentrate in vacuo.Dissolve the residue in ethyl acetate (100 mL), wash with water (2×20mL) and brine (20 mL), dry (Na₂SO₄) the organic phase, filter andconcentrate to afford an oil. Purify the oil by flash chromatography(silica gel, 7×15 cm, ethyl acetate) to afford 0.97 g of4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acidtert-butyl ester as an oil, R_(f)=0.52 (silica gel, ethyl acetate).

Treat a stirred solution of4-(1-vinyl-1H-benzoimidazol-2-yl)-[1,4]diazepane-1-carboxylic acidtert-butyl ester (0.97 g, 2.8 mmol) and methanol (20 mL) at 0° C. with57% hydroiodic acid (467 microliters, 6.21 mmol) solution. Stir at roomtemperatue for two hours, add 57% hydroiodic acid (934 microliters) andreflux for 30 minutes. Cool to room temperature, concentrate in vacuo toapproximately 5 mL final volume, and add ether (total of 200 mL) toafford a tacky solid. Stir the suspension overnight, collect the solidby filtration under nitrogen and dry in vacuo for two hours. Dry invacuo (0.2 Torr) at room temperature overnight to afford 1.33 g of2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoimidazole dihydroiodide.

Reflux a stirred solution of2-[1,4]diazepan-1-yl-1-vinyl-1H-benzoimidazole dihydroiodide (0.70 g,1.40 mmol),1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl-3-phenyl-3-(2-methanesulfonyloxyethyl)-pyrrolidine(0.61 g, 1.3 mmol, example 47.2), triethylamine (4.48 mmol) andacetonitrile (18 mL) under argon for 48 hours. Cool and concentrate invacuo. Thin layer analysis (silica gel, 10% methanol/0.1% ammoniumhydroxide solution in acetonitrile) indicates a mixture with a majorcomponent R_(f)=0.40. Dilute with dichloromethane (150 mL), wash theorganic phase with NaHCO₃ solution (50 mL), dry (Na₂SO₄) the organicphase, filter and evaporate in vacuo. Purify the residue by flashchromatography (silica gel, 7×15 cm) eluting with 10% methanol/0.1%ammonium hydroxide solution in dichloromethane, concentrate theappropriate fractions to afford a tan solid. Purify the solid (in threeseparate injections of 110 mg, 250 mg and 250 mg) by reverse phasechromatography (PrepPak 40×100 mm μBondapak C₁₈, 10 μm, 125 A°, Waters037684, flow rate 35 mL/minute using the following gradients: 5 minuteswith 10% acetonitrile/90% water with 0.1% trifluoroacetic acid, increaseover 30 minutes to 50/50 water/acetonitrile, hold 5 minutes at 50/50water/acetonitrile, increase over 5 minutes to 100% acetonitrile, hold15 minutes at 100% acetonitrile). Combine the desired fractions toafford 0.17 g of the title compound.

PREPARATION 59

2-Methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid

Prepare 5-amino-2-methoxy-benzoic acid methyl ester by catalytichydrogenation of 1-methoxy-5-nitrobenzoic acid methyl ester (103.2 g,0.49 mole, Wychem) over 10%Pd/C (5 g) in methanol (3.1 liters) at 119pounds per square inch pressure. After the uptake of hydrogen ceases,filter the mixture and concentrate the filtrate. Dissolve the residue inethyl acetate (1 liter), wash with saturated brine solution, dry(MgSO₄), filter and concentrate to afford 5-amino-2-methoxy-benzoic acidmethyl ester.

Treat a solution of 5-amino-2-methoxy-benzoic acid methyl ester (7.70 g,42.5 mmol) and dichloromethane (50 mL) portionwise with a solution ofdi-2-pyridyl thionocarbonate (10.0 g, 43.1 mmol; Aldrich ChemicalCompany) and dichloromethane (70 mL) at room temperature under an argonatmosphere. After 3.5 hours, concentrate in vacuo and purify the residueby flash chromatography (silica gel, 5.5×17.8 cm) eluting withdichloromethane. Combine the appropriate fractions and concentrate toafford 5-isothiocyanato-2-methoxy-benzoic acid methyl ester (6.9 g).

Treat a mixture of 5-isothiocyanato-2-methoxy-benzoic acid methyl ester(6.90 g, 30.91 mmol) and formic hydrazide (2.04 g, 34.0 mmol, AldrichChemical Company) under an argon atmosphere via syringe with anhydroustetrahydrofuran (40 mL). After three hours, concentrate in vacuo toremove the solvent, mix the residue with 1 M NaHCO₃ solution (total of300 mL employed) in portions and transfer to a 500 mL round bottomflask. Reflux for 3 days under an argon atmosphere. Filter the hotsolution, acidify with concentrated hydrochloric acid (25 mL), chill themixture in an ice bath and collect the precipitate by vacuum filtration.Wash the filter cake with dichloromethane and dry in vacuo to afford7.12 g of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoicacid. Combine the filtrates and concentrate in vacuo to afford anothercrop of 2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoicacid (1.24 g).

Treat a solution of2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acid(6.66 g, 26.5 mmol) and methanol (80 mL) under argon via syringedropwise with thionyl chloride (2.9 mL, 40 mmol). Stir for three daysand remove the methanol in vacuo. Purify the residue by flashchromatography (silica gel, 9.5×12.7 cm) eluting with 40% ethyl acetatein dichloromethane and then with ethyl acetate. Concentrate the desiredfractions in vacuo to afford 4.55 g of2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acidmethyl ester.

Treat a stirred mixture of2-methoxy-5-(5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-benzoic acidmethyl ester (3.80 g, 14.38 mmol), potassium carbonate (2.19 g, 15.8mmol) and anhydrous acetone (60 mL) with methyl iodide (1.07 mL, 17.25mmol) added dropwise via syringe. Reflux the stirred mixture for 2.5hours, cool, filter and wash the filter cake twice with acetone. Combinethe acetone phases, concentrate in vacuo, dissolve the residue in ethylacetate and wash with NaHCO₃ solution. Extract the combined aqueousphases three times with ethyl acetate. Combine the ethyl acetate phases,wash with saturated NaHCO₃ and brine, dry (MgSO₄), filter andconcentrate in vacuo to afford an oil. Purify the oil by flashchromatography (silica gel, 5.5×15.2 cm) eluting with ethyl acetate andthen with 5% methanol in dichloromethane after elution of the startingmaterial. Concentrate the appropriate fractions to afford 2.89 g of2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methylester as a colorless solid.

Stir a mixture of2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methylester (0.28 g, 3.5 mmol), lithium hydroxide (0.041 g, 3.8 mmol), and 25%water in tetrahydrofuran (20 mL) overnight. Add 1N hydrochloric acid(3.9 mL) dropwise to pH 3. Concentrate to remove the tetrahydrofuran andcollect the precipitate by vacuum filtration. Wash the filter cake twicewith water and hexane, and dry in vacuo overnight to give 0.89 g of2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid as asolid.

EXAMPLE 124

1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-phenyl]-methanone

To a mixture of2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid (0.27 g,0.42 mmol),1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazoledihydrochloride (0.23 g, 0.42 mmol), 1-hydroxybenzotriazole hydrate(0.068 g, 0.51 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(0.97 g, 0.51 mmol), add via syringe under argon anhydrousdichloromethane (15 mL). Add diisopropylethylamine (0.22 mL, 1.26 mmol)and stir at room temperature for 20 hours. Dilute with dichloromethaneand wash twice with water. Wash with saturated NaHCO₃ solution, dry(MgSO₄) the organic phase, filter and concentrate to an oil. Purify theoil by flash chromatography (silica gel, 3.5×15.2 cm) eluting withdichloromethane and then with 10% methanol in dichloromethane.Concentrate the appropriate fractions to afford 0.051 g of the titlecompound, R_(f)=0.26 (silica gel, 10% methanol in dichloromethane). Thecompound may be converted to the dihydrochloride salt by methods wellknown in the art.

PREPARATION 60

5-(3-Methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid

Treat a stirred, chilled (0° C.) solution of2-methoxy-5-(3-methylsulfanyl-[1,2,4]triazol-4-yl)-benzoic acid methylester (1.50 g, 5.4 mmol) and dichloromethane (20 mL) dropwise with asolution of m-chloroperbenzoic acid (2.32 g, 13.5 mmol) anddichloromethane (10 mL). Stir at 0° C. for 30 minutes, then stir at roomtemperature for 64 hours. Concentrate and purify the residue by flashchromatography (silica gel, 5.5×15.2 cm) eluting with ethyl acetate.Combine the appropriate fractions and concentrate in vacuo. Dissolve theresidue in dichloromethane, wash with NaHCO₃ solution, dry (MgSO₄) theorganic phase, filter and concentrate to afford 1.37 g of5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid methylester.

Stir a mixture of5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid methylester (1.0 g, 3.2 mmol), lithium hydroxide (0.042 g, 3.6 mmol), and 25%water in tetrahydrofuran (30 mL) at reflux overnight. Cool and add 1Nhydrochloric acid (3.6 mL) dropwise via syringe. Concentrate to removethe tetrahydrofuran and collect the precipitate by vacuum filtration.Wash the filter cake twice with water and hexane, and dry in vacuoovernight to give 0.79 g of5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid as asolid.

EXAMPLE 125

1-[(R)-3-(2-{4-[1-(2-Ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-[5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-phenyl]-methanone

Condense 5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoicacid (0.125 g, 0.42 mmol) and1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazoledihydrochloride (0.23 g, 0.42 mmol) in the presence of1-hydroxybenzotriazole hydrate (0.062 g, 0.51 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.97 g, 0.51 mmol),diisopropylethylamine (0.22 mL, 1.26 mmol), and dichloromethane (15 mL)as described for the preparation of Example 124 to afford 0.065 g of thetitle compound, R_(f)=0.28 (silica gel, 10% methanol indichloromethane). The compound may be converted to the dihydrochloridesalt by methods well known in the art.

The tachykinins are a class of neuropeptides which share a commonC-terminus sequence, Phe-Xaa-Gly-Leu-Met-NH₂. The tachykinins are widelydistributed in the peripheral and central nervous systems where theybind to at least three receptors types. Among the tachykinin receptors,the NK₁, NK₂, and NK₃ receptors are defined by the preferred bindingaffinity of substance P, neurokinin A (NKA), and neurokinin B (NKB),respectively.

The use of tachykinin antagonists is indicated as therapy for a varietyof tachykinin-mediated diseases and conditions, including:hypersensitivity reactions; adverse immunological reactions; asthma;bronchitis; allergic rhinitis, including seasonal rhinitis andsinusitis; allergies; contact dermatitis; atopic dermatitis;inflammatory bowel diseases, including Crohn's disease and ulcerativecolitis; and emesis.

It is understood that tachykinin-mediated diseases and conditions arethose diseases and conditions in which the tachykinins are involved,either in whole or in part, in their clinical manifestation(s).Moreover, the tachykinins involvement is not necessarily causative of aparticular tachykinin-mediated disease and condition. Tachykininantagonists are useful in controlling or providing therapeutic relief ofthose tachykinin-mediated diseases and conditions.

The present invention provides new and useful tachykinin antagonists offormula (1) or stereoisomers or pharmaceutically acceptable saltsthereof.

In a further embodiment, as tachykinin antagonists the present inventionprovides a method of treating tachykinin-mediated diseases andconditions, including: hypersensitivity reactions; adverse immunologicalreactions; asthma; bronchitis; allergic rhinitis, including seasonalrhinitis and sinusitis; allergies; contact dermatitis; atopicdermatitis; inflammatory bowel diseases, including Crohn's disease andulcerative colitis; and emesis in a patient in need thereof comprisingadministering to said patient a therapeutically effective amount of acompound of formula (1).

Immediate hypersensitivity can occur when an IgE antibody response isdirected against innocuous antigens, such as pollen. During such aresponse there is generally a subsequent release of pharmacologicalmediators, such as histamine, by IgE-sensitized mast cells resulting inan acute inflammatory reaction. The characteristics of the response aredetermined by the tissue in which the reaction occurs and gives rise toallergic diseases including: allergic rhinitis, including seasonalrhinitis and sinusitis; pulmonary diseases, such as asthma; allergicdermatosis, such as urticaria, angioedema, eczema, atopic dermatitis,and contact dermatitis; gastrointestinal allergies, such as those causedby food or drugs; cramping; nausea; vomiting; diarrhea; and ophthalmicallergies, and uveitis.

Histamine, producing its effects via activation of the H₁ receptor, isan important mediator of the above responses involved in immediatehypersensitivity. In the acute phase of allergic rhinitis, histamine H₁receptor antagonists have been shown to effectively inhibit the nasalitchiness, rhinorrhea, and sneezing associated with that condition.However, histamine H₁ receptor antagonists are less effective inrelieving nasal congestion. The acute response to allergen in rhinitisis often followed by a chronic inflammatory response during which theinflamed mucosa becomes hypersensitive to both antigens and nonspecificirritants. Histamine HI receptor antagonists are also ineffective inattenuating the symptoms of the chronic phase of the response.

The present invention provides new and useful histamine antagonists offormula (1) or stereoisomers or pharmaceutically acceptable saltsthereof.

In a further embodiment, as histamine antagonists the present inventionprovides a method of treating allergic diseases, including: allergicrhinitis, including seasonal rhinitis and sinusitis; pulmonary diseases,such as asthma; allergic dermatosis, such as urticaria, angioedema,eczema, atopic dermatitis, and contact dermatitis; allergicconjuctivitis; gastrointestinal allergies, such as those caused by foodor drugs; cramping; nausea; vomiting; diarrhea; and ophthalmic allergiesand uveitis; in a patient in need thereof comprising administering tosaid patient a therapeutically effective amount of a compound of formula(1).

In addition to histamine, the tachykinins, particularly substance P, arealso important contributors to the allergic response and produce somesymptoms distinct from those produced by a histamine response. Thisoccurs because sensory nerves of trigeminal origin, located around bloodvessels and within the nasal mucosal lining, upon stimulation byirritants or inflammatory mediators, such as histamine, will releasetachykinins.

Patients with allergic rhinitis have been shown to have higher nasallevels of substance P when their rhinitis symptoms are present. Mosimannet al. J. Allergy Clin. Immunol. 92, 95 (1993); Takeyama et al., J.Pharm. Pharmacol. 46, 41 (1994); and Wantanabe et al., Ann. Otol.Rhinol. and Laryngol., 102, 16 (1993). Also see Wang, Br. J. Pharmacol.,120, 1491-1496 (1997). In addition, substance P is elevated in the tearsof patients suffering form allergic conjuctivitis. Fujishima, Clin. Exp.Allergy, 27, 372-378 (1997). In humans, topical or intravenousadministration of tachykinins induces nasal obstruction, recruitment ofinflammatory cells, glandular secretion, and microvascular leakage inallergic rhinitis. The nasal obstruction produced by substance P wasfound to be NK₁ receptor mediated. Braunstein et al., Am. Rev. Respir.Dis., 144, 630 (1991); Devillier et al., Eur. Respir. J. 1, 356 (1988).Furthermore, sensory nerve-mediated effects, such as nasal irritabilityand hyperresponsivenesss which occurs in late phase allergic reactions,also result from tachykinin release. Anggard, Acta Otolaryngol. 113, 394(1993). Depletion of tachykinins from nasal sensory nerves after chroniccapsaicin administration improved rhinitic symptoms in affectedindividuals. Lacroix et al., Clin. and Exper. Allergy, 21, 595 (1991).

Antagonism of the effects of histamine on the H₁ receptor is useful inthe treatment of allergic diseases, such as rhinitis. Likewise,antagonism of the effects of the tachykinins, particularly substance Pon its preferred receptor, is useful in the treatment of symptoms whichare concurrent with allergic diseases. Therefore, the potential benefitsof an antagonist with affinity at both the H₁ and NK₁ receptors would beto reduce or prevent clinical manifestations of allergic diseases whichare mediated through both receptors.

More particularly, the present invention provides new and usefulcompounds of formula (1) or stereoisomers or pharmaceutically acceptablesalts thereof which are both tachykinin antagonists and histamineantagonists.

In a further embodiment, as both tachykinin antagonists and histamineantagonists the present invention provides a method of treating allergicdiseases, including: allergic rhinitis, including seasonal rhinitis andsinusitis; contact dermatitis; allergic conjuctivitis; gastrointestinalallergies, such as those caused by food or drugs; cramping; nausea;vomiting; diarrhea; and ophthalmic allergies and uveitis; andinflammatory bowel diseases, including Crohn's diseases and ulcerativecolitis; in a patient in need thereof comprising administering to saidpatient a therapeutically effective amount of a compound of formula (1).

Various diseases and conditions described to be treated herein, are wellknown and appreciated by those skilled in the art. It is also recognizedthat one skilled in the art may affect the associated diseases bytreating a patient presently afflicted with the diseases or byprophylactically treating a patient afflicted with the diseases with atherapeutically effective amount of the compounds of formula (1).

As used herein, the term “patient” refers to a warm blooded animal suchas a mammal which is afflicted with a particular allergic disease. It isunderstood that guinea pigs, dogs, cats, rats, mice, horses, cattle,sheep, and humans are examples of animals within the scope of themeaning of the term.

As used herein, the term “therapeutically effective amount” of acompound of formula (1) refers to an amount which is effective incontrolling the diseases described herein. The term “controlling” isintended to refer to all processes wherein there may be a slowing,interrupting, arresting, or stopping of the progression of the diseasesdescribed herein, but does not necessarily indicate a total eliminationof all disease symptoms, and is intended to include prophylactictreatment of the diseases.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, the dose, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of mammal; itssize, age, and general health; the specific disease involved; the degreeof or involvement or the severity of the disease; the response of theindividual patient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

A therapeutically effective amount of a compound of formula (1) isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are ableto be determined by one skilled in the art.

In effecting treatment of a patient afflicted with diseases describedabove, a compound of formula (1) can be administered in any form or modewhich makes the compound bioavailable in an effective amount, includingoral, inhalation, and parenteral routes. For example, compounds offormula (1) can be administered orally, by inhalation of an aerosol ordry powder, subcutaneously, intramuscularly, intravenously,transdermally, intranasally, rectally, occularly, topically, and thelike. Oral, inhalation, topical, or occular administration is generallypreferred for treatment of allergic diseases. Oral, inhalation, oroccular administration is more preferred for treatment of allergicdiseases. One skilled in the art of preparing formulations can readilyselect the proper form and mode of administration depending upon theparticular characteristics of the compound selected, the disease orcondition to be treated, the stage of the disease or condition, andother relevant circumstances. (Remington's Pharmaceutical Sciences, 18thEdition, Mack Publishing Co. (1990)).

The compounds of the present invention can be administered alone or inthe form of a pharmaceutical composition in combination withpharmaceutically acceptable carriers or excipients, the proportion andnature of which are determined by the solubility and chemical propertiesof the compound selected, the chosen route of administration, andstandard pharmaceutical practice. The compounds of the presentinvention, while effective themselves, may be formulated andadministered in the form of their pharmaceutically acceptable salts,such as acid addition salts or base addition salts, for purposes ofstability, convenience of crystallization, increased solubility, and thelike.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof formula (1) in admixture or otherwise in association with one or morepharmaceutically acceptable carriers or excipients.

The pharmaceutical compositions are prepared in a manner well known inthe pharmaceutical art. The carrier or excipient may be a solid,semi-solid, or liquid material which can serve as a vehicle or mediumfor the active ingredient. Suitable carriers or excipients are wellknown in the art. The pharmaceutical composition may be adapted fororal, inhalation, parenteral, or topical use and may be administered tothe patient in the form of tablets, capsules, aerosols, inhalants,suppositories, solution, suspensions, ointments, or the like.

The compounds of the present invention may be administered orally, forexample, with an inert diluent or with an edible carrier. They may beenclosed in gelatin capsules or compressed into tablets. For the purposeof oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, troches, capsules,elixirs, suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least 4% of the compound of the presentinvention, the active ingredient, but may be varied depending upon theparticular form and may conveniently be between 4% to about 70% of theweight of the unit. The amount of the compound present in compositionsis such that a suitable dosage will be obtained. Preferred compositionsand preparations according to the present invention may be determined bysomeone skilled in the art.

The tablets, pills, capsules, troches and the like may also contain oneor more of the following adjuvants: binders such as microcrystallinecellulose, gum tragacanth or gelatin; excipients such as starch orlactose, disintegrating agents such as alginic acid, Primogel, cornstarch and the like; lubricants such as magnesium stearate or Sterotex;glidants such as colloidal silicon dioxide; and sweetening agents suchas sucrose or saccharin may be added or a flavoring agent such aspeppermint, methyl salicylate or orange flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier such as polyethylene glycol or a fatty oil. Otherdosage unit forms may contain other various materials which modify thephysical form of the dosage unit, for example, as coatings. Thus,tablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the presentcompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors. Materials used in preparing these variouscompositions should be pharmaceutically pure and non-toxic in theamounts used.

For the purpose of parenteral therapeutic administration, the compoundsof the present invention may be incorporated into a solution orsuspension. These preparations should contain at least 0.1% of acompound of the invention, but may be varied to be between 0.1 and about50% of the weight thereof. The amount of the compound of formula (1)present in such compositions is such that a suitable dosage will beobtained. Preferred compositions and preparations are able to bedetermined by one skilled in the art.

The compounds of the present invention may also be administered byinhalation, such as by aerosol or dry powder. Delivery may be by aliquefied or compressed gas or by a suitable pump system which dispensesthe compounds of the present invention or a formulation thereof.

Formulations for administration by inhalation of compounds of formula(1) may be delivered in single phase, bi-phasic, or tri-phasic systems.A variety of systems are available for the administration by aerosol ofthe compounds of formula (1). Dry powder formulations are prepared byeither pelletizing or milling the compound of formula (1) to a suitableparticle size or by admixing the pelletized or milled compound offormula (1) with a suitable carrier material, such as lactose and thelike. Delivery by inhalation includes the necessary container,activators, valves, subcontainers, and the like. Preferred aerosol anddry powder formulations for administration by inhalation can bedetermined by one skilled in the art.

The compounds of the present invention may also be administeredtopically, and when done so the carrier may suitably comprise asolution, suspension, ointment, or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Topical formulations may contain aconcentration of the formula (1) or its pharmaceutical salt from about0.1 to about 10% w/v (weight per unit volume).

The solutions or suspensions may also include one or more of thefollowing adjuvants: sterile diluents such as water for injection,saline solution, fixed oils, polyethylene glycols, glycerine, propyleneglycol or other synthetic solvents; antibacterial agents such as benzylalcohol or methyl paraben; antioxidants such as ascorbic acid or sodiumbisulfite; chelating agents such as ethylene diaminetetraacetic acid;buffers such as acetates, citrates or phosphates and agents for theadjustment of tonicity such as sodium chloride or dextrose. Theparenteral preparation can be enclosed in ampules, disposable syringesor multiple dose vials made of glass or plastic.

EXAMPLE A

Antagonism of [³H]-pyrilamine binding to histamine H₁ receptors byputative antagonists

One skilled in the art can measure the H₁ receptor affinity of proposedhistamine antagonists as evaluated in rat brains or Chinese hamsterovary cells transfected with the human histamine H₁ receptor gene(CHOpcDNA3H1R cells).

For the studies in rat brain, young male rats are sacrificed bydecapitation and the brains are immediately removed. The cortici aredissected and used immediately or stored at −20° C. For the studies inChinese hamster ovary cells, confluent cells are freshly scraped fromculture flasks. The tissues or cells are homogenized with a Polytron(setting no. 6 for 15 seconds) in 20 mL of 50 mM potassium sodiumphosphate (pH 7.4, at 4° C.). The homogenate is centrifuged at 48,000×gfor 12 minutes at 4° C. The pellet is resuspended using a Polytron(setting no. 6 for 15 seconds) in incubation buffer (50 mM potassiumsodium phosphate, pH 7.4, at ambient temperature, containing 0.1% bovineserum albumin) to a concentration of 40 mg/mL and is immediately addedto tubes to start the assay. The protein content of the crude membranesuspension can be determined by the method of O. H. Lowery et al., J.Biol. Chem., 193 265 (1951).

The binding assay is carried out in duplicate or triplicate in 12×75 mmpolypropylene tubes in 50 mM potassium sodium phosphate (pH 7.4, atambient temperature) containing 0.1% bovine serum albumin. Theradioligand, [³H]-pyrilamine, is diluted in incubation buffer to aconcentration of 2 nM and added to each tube (50 μL). The test compoundis diluted in incubation buffer (10⁻¹⁰ M to 10⁻⁵ M) and is added to theappropriate tubes (50 μL). The assay is started by the addition of 250μL of well mixed tissue suspension. The final incubation volume is 0.5mL. The assay is carried out at ambient temperature for 30 minutes. Theincubation is terminated by the addition of 3.5 mL of 0.9% sodiumchloride solution (4° C.) and filtration through GF/B filters that havebeen presoaked overnight in 0.1% polyethyleneimine, using a Brandel cellharvester. The filters are rapidly washed with two 3.5 mL portions ofincubation buffer and transferred to scintillation vials. Ecolume (9 mL)is added the the vials. the vials are shaken and allowed to set for 4hours before being counted by liquid scintillation spectrometry.Specific binding is determined bas the difference between tubescontaining no test compound and the the tubes containing 10 μMpyrilamine. Total membrane bound radioactivity is generally about 5% ofthat added the the tubes. Specific binding is generally 75% to 90% oftotal binding as determined by the method of M. D. DeBacker et al.,Biochem. and Biophys. Res. Commun., 197(3) 1601 (1991).

The molar concentration of compound that causes 50% inhibition ofradioligand binding. The IC₅₀ value is generated for each test compoundby nonlinear regression using an iterative curve fitting program (GraphPAD Inplot, San Diego, Calif.).

EXAMPLE B

Antagonism of iodinated tachykinin binding to NK₁ receptors by putativeantagonists

One skilled in the art can measure the NK₁ receptor affinity of proposedtachykinin antagonists as evaluated in guinea pig lungs (KeystoneBiologicals, Cleveland, Ohio). Tissues are homogenized with a Polytronin 15 volumes of 50 mM Tris-HCl buffer (pH 7.4, 4° C.) and centrifuged.The pellet is resuspended in Tris-HCl buffer and centrifuged; the pelletis washed twice by resuspension. The final pellet is resuspended at aconcentration of 40 mg/ml incubation buffer and remains at roomtemperature for at least 15 min prior to use.

Receptor binding is initiated by addition of 250 μl membrane preparationin duplicate to 0.1 nM of ¹²⁵I-Bolton Hunter Lys-3 labeled substance Pin a final volume of 500 μl of buffer containing 50 mM Tris-HCl (pH 7.4at room temperature), 0.1% bovine serum albumin, 2 mM MnCl₂, 40 μg/mlbacitracin, 4 μg/ml leupeptin and chymostatin, 1 μM thiorphan andvarious doses of the putative tachykinin antagonists. Incubations areperformed at room temperature for 90 min; binding is terminated byaddition of 50 mM Tris-HCl buffer (pH 7.4, 4° C.) and filtration undervacuum through GF/B filters presoaked with 0.1% polyethyleneimine.Filter bound radioactivity is quantitated in a gamma counter.Nonspecific binding is defined as binding in the presence of 1 μMsubstance P.

Specific binding is calculated by subtracting nonspecific binding fromtotal binding. Competition of iodinated substance P binding by testcompounds or standards is expressed as a percentage of this maximumcompetition. IC₅₀ values (concentration required to inhibit 50% ofreceptor binding) are generated for each of the test compounds bynonlinear regression using an iterative curve fitting program (GraphPADInplot, San Diego, Calif.).

EXAMPLE C

Histamine (H₁) antagonism in guinea pig ileum

One skilled in the art can determine that the compounds of the presentinvention are H₁ receptor antagonists in vitro by evaluating thecompound's ability to inhibit histamine mediated smooth musclecontraction. Male Hartley guinea pigs, weighing 200-450 grams, aresacrificed by CO₂ asphyxiation. A piece of ileum, about 20 cm in length,is removed and cut into 2 cm pieces. Each ileum piece is placed in anorgan bath at 37° C. containing Tyrode's solution and is constantlyaerated with 95% O₂/5% CO₂. Tyrode's solution has the composition:sodium chloride 136.9 mM, potassium chloride 2.68 nM, calcium chloride1.8 mM, sodium dihydrogen phosphate 0.42 mM, sodium bicarbonate 11.9 mM,and dextrose 5.55 mM. Contractions are measured with an isometrictransducer (Grass FTO3C), and are recorded on a polygraph recorderand/or a computer. The ileum strips are loaded with 1.0 grams of tensionand allowed to equilibrate for a minimum of 30 minutes before startingthe experiments. Tissue are preincubated with vehicle or varyingconcentrations of test compound followed by histamine challenge.

A competitive H₁ receptor antagonist produces a parallel shift of thehistamine dose-response curve to the right without a depression of themaximal response.

The potency of the antagonism is determined by the magnitude of theshift and is expressed as a pA₂ value which is the negative logarithm ofthe molar concentration of antagonist which produces a two-fold shift ofthe dose response curve to the right. The pA₂ value is calculated byusing Schild analysis. O. Arunlakshana and H. O. Schild, Br. J.Pharmacol Chemother. 14, 48-58 (1958). When the slope of the linesobtained by a Schild analysis are not significantly different from one(1) the compound is acting as a competitive antagonist.

EXAMPLE D

Antagonism of Tachykinin-induced phosphatidylinositol (PI) turnover invitro by putative antagonists

One skilled in the art can determine NK₁ receptor antagonism bymeasuring the substance P-induced phosphatidylinositol (PI, inositolphosphate) accumulation in UC11 cells in the presence and absence of NK₁or NK₂ receptor antagonists. Cells are seeded onto 24-well plates at125,000 cells/well, two or three days prior to the assay. Cells areloaded with 0.5 mL of 0.2 μM myo-[2-³H(N)]inositol (AmericanRadiolabeled Chemicals Inc., specific activity; 20 μCi/mmol) 20-24 hoursprior to the assay. Cultured cells are maintained at 37° C. in 5% CO₂environment.

On the day of the assay, media is aspirated and the cells incubated inRPMI-1640 media containing 40 μg/ml bacitracin, 4 μg/ml each ofleupeptin and chymostatin, 0.1% bovine serum albumin, 10 μM thiorphan,and 10 mM lithium chloride. After 15 minutes, the test compound is addedto the cells in a volume of 0.1 mL. After another 15 min, substance P isadded to UC11 cells at various concentrations to start the reactionfollowed by incubation for 60 min at 37° C. in 5% CO₂ environment in afinal volume of 1 mL. To terminate the reaction, the media is aspiratedand methanol (0.1 mL) is added to each well. Two aliquots of methanol(0.5 mL) are added to the wells to harvest the cells into chloroformresistant tubes. Chloroform (1 mL) is added to each tube followed bydoubly distilled water (0.5 mL). Samples are vortexed for 15 seconds andcentrifuged at 1700×g for 10 minutes. An aliquot (0.9 mL) of the aqueous(top) phase is removed and added to doubly distilled water (2 mL). Themixture is vortexed and loaded onto a 50% Bio-Rad AG 1-X8 (formate form,100-200 mesh) exchange column (Bio-Rad Laboratories, Hercules, Calif.).The columns are washed, in order, with: 1) 10 ml doubly distilled water,2) 5 mL of 5 mM disodium tetraborate/60 mM sodium formate, and 3) 2 mLof 1 M ammonium formate/0.1 M formic acid. The third elution iscollected and counted in 9 mL scintillation fluid. A 50 μl aliquot ofthe organic (bottom) phase is removed, dried in a scintillation vial andcounted in 7 mL scintillation fluid.

The ratio of DPM in the aqueous phase aliquot (total inositolphosphates) to the DPM in the 50 μl organic phase aliquot (total[³H]inositol incorporated) is calculated for each sample. Data areexpressed as a percent of agonist-induced accumulation of [³H]-inositolphosphates over basal levels. The ratios in the presence of testcompound and/or standards are compared to the ratios for control samples(i.e. no stimulating agonist).

Dose-response graphs are constructed and the ability of the testcompounds to inhibit tachykinin-induced phosphatidyinositol turnoverdetermined with the aid of a computer program. Data is expressed aspercent stimulation of total inositol phosphate accumulation over basallevels and normalized to the maximum response produced by substance P.Schild analysis is performed using dose response curves to obtain avalue indicative of the strength of a competitive antagonist and isexpressed as the pA₂, which is the negative logarithm of the molarconcentration of antagonist which reduces the effect of a dose ofagonist to one-half of that expected at the dose of agonist. When theslope of the lines obtained by a Schild analysis are not significantlydifferent from one (1) the compound is acting as a competitiveantagonist.

EXAMPLE E

Evaluation of H₁ (or NK₁) antagonism in vivo

One skilled in the art can determine that the compounds of the presentinvention mediate the immediate hypersensitivity response in vivo byevaluating the ability of the compounds to inhibit the formation ofhistamine (or substance P) induced wheals in guinea pigs. Animals areanesthetized with pentobarbital (i.p.). Dorsal skin is shaved andintradermal injections of histamine (or substance P) are given in theshaved area at appropriate times after the administration of the testcompounds. Doses, routes, and times of administration may vary accordingto experimental design. The design of such experiments is well known andappreciated in the art. Immediately after the intradermal challenges,the animal is given an intravenous injection of 1% Evan's blue dye tomake the wheals visible. At an appropriate time after the challenge theanimals are sacrificed by CO₂ inhalation. The skin is removed and thediameter of each wheal is measured in two perpendicular directions.

The wheal response is used an the index of the edema response. Thepercent of inhibition of the wheal response is calculated by comparingthe drug-treated group to a vehicle treated group. Linear regression ofthe dose-response inhibition curve is used to determine an ED₅₀ value,expressed in mg/kg.

EXAMPLE F

Evaluation of NK₁ antagonism in vivo

One skilled in the art can also determine that the compounds of thepresent invention are NK₁ receptor antagonists in vivo by evaluating thecompound's ability to inhibit substance P-induced plasma proteinextravasation in guinea pig trachea. Substance P-induced protein leakagethrough postcapillary venules is assessed by measuring Evans Blue dyeaccumulation in guinea pig trachea. Animals are anesthetized withpentobarbitol then injected with Evans Blue dye (20 mg/kg, i.v.,prepared in 0.9% sodium chloride solution). One minute after dyeadministration, the antagonist is administered (i.v.) followed bysubstance P (0.3 mmole/kg, i.v.) and, after 5 min, excess dye removedfrom the circulation by transcardiac perfusion with 50 ml 0.9% sodiumchloride solution. The trachea and primary bronchi are removed, blotteddry and weighed.

Dye quantitation is performed spectrophotometrically (620 nm) afterextracting tissues in formamide for 24 hr at 50° C. Values aresubtracted from background (dye only, no agonist). ED₅₀ (dose ofcompound which inhibits substance P-induced plasma protein extravasationby 50%) is calculated from linear regression analysis.

What is claimed is:
 1. A compound, including enantiomers, stereoisomers,rotomers and tautomers of said compound and pharmaceutically acceptablesalts, solvates or derivatives thereof, with said compound having thegeneral structure shown in the formula:

wherein m is 2 or 3; A is 1 or 2; G is —C(O)—, —C(O)—CH₂—, or —SO₂—; R₃₀is selected from the group consisting of: —C₅-C₈ alkyl, —(CH₂)_(p)CF₃,vinyl,

wherein p is an integer from 1 to 4; B is an integer from 1 to 4; D isan integer from 1 to 4; s is an integer from 1 to 4; and R₃₄ is C₁-C₄alkyl; R₃₁ and R₃₂ are the same or different and are independentlyselected from hydrogen or C₁-C₄ alkoxy; and R₃₃ is selected from thegroup consisting of: hydrogen, C₁-C₄ alkoxy,

wherein E is an integer from 2 to
 4. 2. The compound as set forth inclaim 1 which is1-((R)-3-(2-(4-(1-(2-cyclopropylmethoxyethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 3. Thecompound as set forth in claim 1 which is1-((R)-3-(2-(4-(1-cyclopropylmethyl-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 4. Thecompound as set forth in claim 1 which is1-(2-methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-(2-(4-(1-(2-(5-methyl-tetrazol-1-yl)-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 5. Thecompound as set forth in claim 1 which is1-((R)-3-(2-(4-(1-(2-(2-methoxy-ethoxy)ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 6. Thecompound as set forth in claim 1 which is1-(2-methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-(2-(4-(1-(2-methyl-thiazol-4-ylmethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 7. Thecompound as set forth in claim 1 which is1-(2-methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-(2-pyrazol-1-yl-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-pyrrolidin-1-yl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 8. Thecompound as set forth in claim 1 which is methanesulfonic acid3-(1-((R)-3-(2-(4-(1-(2-ethoxy-ethyl)-1H-berizoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanoyl)-4-methoxy-phenylester having the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 9. Thecompound as set forth in claim 1 which is1-((R)-3-(2-(4-(1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-(2-methoxy-ethoxy)-phenyl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 10. Thecompound as set forth in claim 1 which is1-(2-methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-(2-)4-(1-pentyl-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 11. Thecompound as set forth in claim 1 which is1-(3-(1-((R)-3-(2-(4-(1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)methanoyl)-4-methoxy-phenoxy)-propan-2-onehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 12. Thecompound as set forth in claim 1 which is1-(2-methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-(2,2,2-trifluoro-ethyl)-H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-pyrrolidin-1-yl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 13. Thecompound as set forth in claim 1 which is1-(2-methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-(4,4,4-trifluoro-butyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-pyrrolidin-1-yl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 14. Thecompound as set forth in claim 1 which is1-(2-methoxy-5-tetrazol-1-yl-phenyl)-1-((R)-3-phenyl-3-(2-(4-(1-vinyl-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl(-ethyl)-pyrrolidin-1-yl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 15. Thecompound as set forth in claim 1 which is methanesulfonic acid4-(1-((R)-3-(2-(4-(1-2(ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-methanoyl)-2,6-dimethoxy-phenylester hydrochloride having the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 16. Thecompound as set forth in claim 1 which is1-((R)-3-(2-(4-(1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-1-(2-methoxy-5-(3-methylsulfanyl-(1,2,4)triazol-4-yl)-phenyl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 17. Thecompound as set forth in claim 1 which is1-((R)-3-(2-(4-(1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-pyrrolidin-1-yl)-1-(5-(3-methanesulfonyl-(1,2,4)triazol-4-yl)-2-methoxy-phenyl)-methanonehaving the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 18. Thecompound as set forth in claim 1 which is2-(4-(2-((R)-1-(2,5-dimethoxy-benzenesulfonyl)-3-phenyl-pyrrolidin-3-yl)-ethyl)-(1,4)dizaepan-1-yl)-1-(2-ethoxy-ethyl)-1H-benzoimidazolehydrochloride having the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 19. Thecompound as set forth in claim 1 which is1-(3-(2-(4-(1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl)-(1,4)diazepan-1-yl)-ethyl)-3-phenyl-azetidin-1-yl)-2-(3,4,5-trimethoxy-phenyl)-ethanonehydrochloride having the formula:

or a pharmaceutically acceptable acid addition salt thereof.
 20. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 21. A method for treating allergicrhinitis in a patient in need thereof comprising administering to saidpatient a therapeutically effective amount of a compound of claim
 1. 22.A method for treating asthma in a patient in need thereof comprisingadministering to said patient a therapeutically effective amount of acompound of claim
 1. 23. A method for treating emesis in a patient inneed thereof comprising administering to said patient a therapeuticallyeffective amount of a compound of claim
 1. 24. A method for treatinguieitis in a patient in need thereof comprising administering to saidpatient a therapeutically effective amount of a compound of claim
 1. 25.A method for treating allergic conjuctivitis in a patient in needthereof comprising administering to said patient a therapeuticallyeffective amount of a compound of claim
 1. 26. A method for treatingophthalmic allergies in a patient in need thereof comprisingadministering to said patient a therapeutically effective amount of acompound of claim
 1. 27. A method for treating inflammatory boweldisease in a patient in need thereof comprising administering to saidpatient a therapeutically effective amount of a compound of claim 1.